safety assessment of brown algae-derived ingredients as used … algae_1.pdf · status: draft final...

Safety Assessment of Brown Algae-Derived Ingredients

as Used in Cosmetics

Status: Draft Final Report for Panel Review Release Date: March 15, 2019 Panel Meeting Date: April 8-9, 2019

The 2019 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Ronald A. Hill, Ph.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; James G. Marks, Jr., M.D.; Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Executive Director is Bart Heldreth, Ph.D. This report was prepared by Lillian C. Becker, former Scientific Analyst/Writer and Priya Cherian, Scientific Analyst/Writer.

© Cosmetic Ingredient Review 1620 L Street, NW, Suite 1200 ♢ Washington, DC 20036-4702 ♢ ph 202.331.0651 ♢ fax 202.331.0088

[email protected]

mailto:[email protected]

__________________________________________________________________________________________ 1620 L St NW, Suite 1200, Washington, DC 20036

(Main) 202-331-0651 (Fax) 202-331-0088 (Email) [email protected] (Website) www.cir-safety.org

Commitment & Credibility since 1976

Memorandum

To: CIR Expert Panel Members and Liaisons From: Priya Cherian, Scientific Writer/Analyst Date: March 15, 2019 Subject: Draft Final Report of the Safety Assessment on Brown Algae-Derived Ingredients Enclosed is the Draft Final Report of the Safety Assessment of Brown Algae-Derived Ingredients as Used in Cosmetics. (It is identified as broalg042019rep in the pdf document). At the December 2018 meeting, the Panel concluded that 6 of the 82 brown algae-derived ingredients are safe in cosmetics in the present practices of use and concentration described in the safety assessment. These ingredients include Alaria Esculenta Extract, Laminaria Digitata Extract, Laminaria Saccharina Extract, Macrocystis Pyrifera (Kelp) Extract, Undaria Pinnatifida Extract, and Undaria Pinnatifida Cell Culture Extract. The Panel came to this conclusion by assessing the systemic toxicity potential (either in repeated dose studies or GRAS status/use in food) and sensitization data of the ingredients. The Panel concluded that the data are insufficient to determine the safety of the remaining ingredients under the intended conditions of use in cosmetic formulations. In order to analyze the safety of these remaining ingredients, the following data are needed:

• Systemic toxicity data • Sensitization data

Although this safety assessment includes 82 brown algae-derived ingredients, it should be noted that several of these ingredients appear to be equivalent based on the accepted scientific name, as given in the definition by the wINCI Dictionary. Accordingly, the total number of distinct cosmetic ingredients is 74. Table 1 in the report has been updated to include all 82 ingredients, along with their respective synonymous names. Since the December Panel meeting, CIR has received the following data, which have been incorporated into the report and have been designated by highlighting (broalg042019data1 through broalg042019data15).

• broalg042019data 1: summary of edible seaweeds and French regulations • broalg042019data2: dermal toxicity, sensitization, solvent information, and arsenic/iodine impurities data on

several brown algae-derived ingredients (summary information from UNITIS) • broalg042019data3: human sensitization data on a cream containing Cystoseira

Amentacea/Caespitosa/Branchycarpa Extract and a cream containing Himanthalia Elongata Extract • broalg042019data4: specifications, method of manufacturing information, heavy metal impurities, ocular irritation

data, and dermal irritation data for a mixture containing water, Himanthalia Elongata Extract, Fucus Vesiculosus Extract, and saccharomyces cerevisiae extract

• broalg042019data5: specifications, method of manufacturing information, heavy metal impurities, ocular irritation data, and dermal irritation data for a mixture containing caprylic/capric triglyceride, Laminaria Ochroleuca Extract, and tocopherol

• broalg042019data6: specifications, method of manufacturing information, heavy metal impurities, ocular irritation data, and dermal irritation data for a mixture containing water, Ascophyllum Nodosum Extract, and Halopteris Scoparia Extract

Distributed for Comment Only -- Do Not Cite or Quote


http://www.cir-safety.org/

__________________________________________________________________________________________ 1620 L St NW, Suite 1200, Washington, DC 20036

(Main) 202-331-0651 (Fax) 202-331-0088 (Email) [email protected] (Website) www.cir-safety.org

• broalg042019data7: specifications, method of manufacturing information, heavy metal impurities, ocular irritation data, and dermal irritation data for a mixture containing water and Fucus Serratus Extract

• broalg042019data8: specifications, method of manufacturing information, heavy metal impurities, ocular irritation data, and dermal irritation data for a mixture containing water, butylene glycol, and Lessonia Nigrescens Extract

• broalg042019data9: specifications, method of manufacturing information, heavy metal impurities, ocular irritation data, dermal irritation data, a bacterial reverse mutation assay, and sensitization data for a mixture containing water, Fucus Spiralis Extract, and tetraselmis chi extract

• broalg042019data10: specifications, method of manufacturing information, heavy metal impurities, ocular irritation data, and dermal irritation data for a mixture containing water and Sargassum Muticum Extract

• broalg042019data11: specifications, method of manufacturing information, heavy metal impurities, ocular irritation data, dermal irritation data, and sensitization data for a mixture containing water and Pelvetia Canaliculata Extract

• broalg042019data12: sensitization data of a trade name mixture containing Fucus Vesiculosus Extract • broalg042019data13: composition data and sensitization data of a trade name mixture containing Sargassum

Filipendula Extract • broalg042019data14: updated use information for Halidrys Siliquosa Extract • broalg042019data15: additional dose information on UNITIS HRIPTs

As the inclusion of this new data may help the Panel decide on a conclusion of safety for several more of these brown-algae derived ingredients, a table has been provided presenting each ingredient, as well as a notation of the presence or absence of systemic toxicity data (repeated dose studies or use in food/as a GRAS substance) and sensitization data. This table can be found in the packet as broalg042019data16. Comments provided by the Council before and after the December meeting on the Tentative Report have been addressed (broalg042019pcpc1, broalg042019pcpc2, broalg042019pcpc3, and broalg042019pcpc4). Comments received from the CIR SSC (broalg042019pcpc2) suggest that “knowing the major constituents of an ingredient should also be a route to a safe conclusion.” Does the Panel agree with this suggestion? If this suggestion is accepted, then it is important to emphasize that the conclusion applies to the material as described in the CIR safety assessment. In addition, the flow chart (broalg042019flow), updated data profile (broalg042019prof), 2019 VCRP data (broalg042019FDA), minutes (broalg042019min), history (broalg042109hist), and search strategy (broalg042019strat), have been included in this packet. The Panel should carefully consider the Abstract, Discussion, and data presented in this report. If the Panel determines that the information that was received since the Tentative Report was issued satisfies the data needs for additional ingredients, then those ingredients should be identified, and a revised Tentative Report should be issued. If the data that were received do not change the conclusion, then a Final Report with the current split conclusion should be issued.



http://www.cir-safety.org/

SAFETY ASSESSMENT FLOW CHART

INGREDIENT/FAMILY _Brown Algae-derived ingredients ______________________________

MEETING ___April 2019 ___________________________________________________________

Public Comment CIR Expert Panel Report Status

Priority List INGREDIENT

PRIORITY LIST

SLR

July 26, 2018

60 day public comment period

Draft Report

Table IDA TR

IDA Notice IDA

Draft TR

Table

Tentative Report Jan 9, 2019

60 day Public comment period

Draft FR

Table Different Conclusion

PUBLISH Final Report

DRAFT REPORT Sept 2018

DRAFT TENTATIVE REPORT

Dec 2018

DRAFT FINAL REPORT Apr 2019

Issue TR

Issue FR

Table

Table

Table


History of Brown Algae

August 2018: SLR announced for public comment

September 2018: draft report reviewed by Panel; the Panel issued an IDA; the Panel requested the following data:

• Composition and organic constituent data for each of these Brown Algae-derived cosmetic ingredients • 28-Day dermal toxicity data for those ingredients that are not GRAS • Sensitization data at relevant use concentrations for all ingredients (e.g., Macrocystis Pyrifera (Kelp)

Extract at 36.4%) • Genotoxicity data for those ingredients that are not GRAS

Following the September 2018 meeting, information regarding manufacturing, composition, genotoxicity, sensitization, skin irritation, and ocular irritation regarding several brown algae ingredients were received.

December 2018: the Panel reviews the draft tentative report; issues a safe as used conclusion for 6 of the 82 ingredients, and insufficient conclusion for the remaining ingredients. The Panel requested systemic toxicity data and sensitization data for these remaining ingredients

January/February 2019: Comments received from Council; Data received from Council regarding manufacturing, composition, genotoxicity, sensitization, skin irritation, and eye irritation of several brown algae ingredients

April 2019: Panel reviews the draft Final report


Brown Algae Data Profile for April 2019. Writer – Priya Cherian

ADME Acute toxicity

Repeated dose toxicity Irritation Sensitization

Use

Log Kow

Derm

al P

enetration

Oral

Derm

al

Inhale

Oral

Derm

al

Inhale

Ocular A

nimal

Ocular In V

itro

Derm

al Anim

al

Derm

al Hum

an

Derm

al In Vitro

Anim

al

Hum

an

In Vitro

Repro/D

evel

Genotoxicity

Carcinogenicity

Phototoxicity

1. Agarum Cribrosum Extract x 2. Alaria Esculenta Extract x

x x x

3. Ascophyllum Nodosum x 4. Ascophyllum Nodosum

Extract x x x x x x x x x

5. Ascophyllum Nodosum Powder

x x

6. Cladosiphon Novae-Caledoniae Extract

7. Cladosiphon Okamuranus Extract

x

8. Cystoseira Amentacea/Caespitosa/ Branchycarpa Extract

x x x x

9. Cystoseira Baccata Extract x x 10. Cystoseira Balearica

Extract

11. Cystoseira Caespitosa Extract

12. Cystoseira Compressa Extract

x x

13. Cystoseira Compressa Powder

14. Cystoseira Tamariscifolia Extract

x x

15. Dictyopteris Membranacea Extract (Retired)

16. Dictyopteris Polypodioides Extract

x x x

17. Dictyota Coriacea Extract 18. Durvillea Antarctica Extract x 19. Ecklonia Cava Extract x x x 20. Ecklonia Cava Water x 21. Ecklonia Kurome Extract 22. Ecklonia Kurome Powder 23. Ecklonia/Laminaria Extract 24. Ecklonia Maxima Extract 25. Ecklonia Maxima Powder 26. Ecklonia Radiata Extract x 27. Eisenia Arborea Extract 28. Fucus Serratus Extract x x x 29. Fucus Spiralis Extract x x x x x 30. Fucus Vesiculosus x 31. Fucus Vesiculosus Extract x

x x x x x x x x

32. Fucus Vesiculosus Powder x 33. Halidrys Siliquosa Extract x x x x x 34. Halopteris Scoparia Extract x x x 35. Himanthalia Elongata

Extract x x x

36. Himanthalia Elongata Powder

x

37. Hizikia Fusiforme Extract x 38. Hizikia Fusiformis Water



ADME Acute toxicity


Use

Log Kow

Derm

al P

enetration

Oral

Derm

al

Inhale

Oral

Derm

al

Inhale

Ocular A

nimal

Ocular In V

itro

Derm

al Anim

al

Derm

al Hum

an

Derm

al In Vitro

Anim

al

Hum

an

In Vitro

Repro/D

evel

Genotoxicity

Carcinogenicity

Phototoxicity

39. Hizikia Fusiformis Callus Culture Extract

40. Hydrolyzed Ecklonia Cava Extract

41. Hydrolyzed Fucus Vesiculosus Extract

42. Hydrolyzed Fucus Vesiculosus Protein

43. Kappaphycus Alvarezii Extract

44. Laminaria Angustata Extract (Retired)

45. Laminaria Cloustoni Extract x 46. Laminaria Diabolica Extract 47. Laminaria Digitata Extract x x x

x x x

48. Laminaria Digitata Powder x 49. Laminaria Hyperborea

Extract x x x

50. Laminaria Japonica Extract x x x x x 51. Laminaria Japonica Powder x 52. Laminaria Longissima

Extract

53. Laminaria Ochotensis Extract (Retired)

54. Laminaria Ochroleuca Extract

x x x

55. Laminaria Saccharina Extract

x x x

56. Lessonia Nigrescens Extract

x x x

57. Lessonia Nigrescens Powder

58. Macrocystis Pyrifera (Kelp) x x x x 59. Macrocystis Pyrifera (Kelp)

Blade/Pneumatocyst/Stipe Juice Extract

60. Macrocystis Pyrifera (Kelp) Extract

x x x

61. Macrocystis Pyrifera (Kelp) Juice

62. Macrocystis Pyrifera (Kelp) Protein

x

63. Nereocystis Luetkeana Extract

x x

64. Pelvetia Canaliculata Extract

x x x x

65. Pelvetia Siliquosa Extract 66. Phyllacantha Fibrosa

Extract x x

67. Saccharina Angustata Extract

x

68. Saccharina Japonica Extract

69. Saccharina Longicruris Extract



ADME Acute toxicity


Use

Log Kow

Derm

al P

enetration

Oral

Derm

al

Inhale

Oral

Derm

al

Inhale

Ocular A

nimal

Ocular In V

itro

Derm

al Anim

al

Derm

al Hum

an

Derm

al In Vitro

Anim

al

Hum

an

In Vitro

Repro/D

evel

Genotoxicity

Carcinogenicity

Phototoxicity

70. Sargassum Filipendula Extract

x x x x x

71. Sargassum Fulvellum Extract

x

72. Sargassum Fusiforme Extract

73. Sargassum Glaucescens Extract

x

74. Sargassum Horneri Extract 75. Sargassum Muticum

Extract x x x

76. Sargassum Pallidum Extract

x

77. Sargassum Siliquastrum Extract

78. Sargassum Thunbergii Extract

79. Sargassum Vulgare Extract x 80. Sphacelaria Scoparia

Extract x x x

81. Undaria Peterseniana Extract

82. Undaria Pinnatifida Extract x x x x x 83. Undaria Pinnatifida Cell

Culture Extract x x x x

84. Undaria Pinnatifida Leaf/Stem Extract

x

85. Undaria Pinnatifida Powder x x x 86. Undaria Pinnatifida Root

Powder


Brown Algae Ingredient CAS # InfoBase SciFinder PubMed TOXNET FDA EU ECHA IUCLID SIDS HPVIS NICNAS NTIS NTP WHO FAO FEMA Web 1. Agarum Cribrosum

Extract - - X X X X X X N N N n n √

2. Alaria Esculenta Extract

- - X X X X X X √

3. Ascophyllum Nodosum

- - √ X √ X X X √

4. Ascophyllum Nodosum Extract

84775-78-0 √ √ X √ X X C √


- - √ X X X X X √

6. Asterionellopsis Glacialis Extract

- - X X X X X X X


- - X X X X X X X


- - X X X X X X

9. Cystoseira Amentacea/ Caespitosa/ Branchycarpa Extract

- - X X X X X X

10. Cystoseira Baccata Extract

- - X X X X X X

11. Cystoseira Balearica Extract

- - X X X X X X


- - X X X X X X


- - X √ X X X X


- - X X X X X X


- - X X X X X X


- - X √ X X X X


- - X X X X X X

18. Dictyota Coriacea Extract

- - X X X X X X

19. Durvillea Antarctica Extract

- - X X X X X X

20. Ecklonia Cava Extract

- - X √ X X X X


Ingredient CAS # InfoBase SciFinder PubMed TOXNET FDA EU ECHA IUCLID SIDS HPVIS NICNAS NTIS NTP WHO FAO FEMA Web 21. Ecklonia Cava Water - - X X X X X X

22. Ecklonia Kurome Extract

- - X X X X X X

23. Ecklonia Kurome Powder

- - X X X X X X

24. Ecklonia/Laminaria Extract

- - X X X X X X

25. Ecklonia Maxima Extract

- - X X X X X X

26. Ecklonia Maxima Powder

- - X X X X X X

27. Ecklonia Radiata Extract

- - X X X X X X

28. Eisenia Arborea Extract

- - X X X X X X

29. Fucus Serratus Extract

94167-02-9 - √ √ X X X X

30. Fucus Spiralis Extract

- - √ X X X X X

31. Fucus Vesiculosus - - X √ √ X X X

32. Fucus Vesiculosus Extract

283-633-7 √ X X X X X X

33. Fucus Vesiculosus Powder

- √ X √ X X X X

34. Halidrys Siliquosa Extract

- - X X X X X X

35. Halopteris Scoparia Extract

- - X X X X X X

36. Himanthalia Elongata Extract

- - X X √ X X X


- - X X X X X X

38. Hizikia Fusiforme Extract

- - X X √ X X X

39. Hizikia Fusiformis Water

- - X X X X X X


- - X X X X X X


- - X X X X X X


84696-13-9 - √ X X X X X


- - X X X X X X

44. Kappaphycus Alvarezii Extract

1220882-73-4 (generic)

- X X X X X X


Ingredient CAS # InfoBase SciFinder PubMed TOXNET FDA EU ECHA IUCLID SIDS HPVIS NICNAS NTIS NTP WHO FAO FEMA Web 45. Laminaria Angustata

Extract (Retired) - √ X X X X X X

46. Laminaria Cloustoni Extract

90046-11-0

92128-82-0 - X X X X X X

47. Laminaria Diabolica Extract

- - X X X X X X

48. Laminaria Digitata Extract

90046-12-1

92128-82-0

√ √ X √ √ X X

49. Laminaria Digitata Powder

- √ X X X √ X X

50. Laminaria Hyperborea Extract

90046-13-2

92128-82-0

√ √ X √ √ X X

51. Laminaria Japonica Extract

92128-82-0 √ √ √ √ √ X X

52. Laminaria Japonica Powder

- - X X X X X X

53. Laminaria Longissima Extract

- - X X X X X X


- √ X X X √ X X


92128-82-0 - √ X X X X X


90046-14-3

92128-82-0

√ √ X X √ X X


- - X X X X X X


- - X X X X X X

59. Macrocystis Pyrifera (Kelp)

- √ √ X X X X X

60. Macrocystis Pyrifera (Kelp) Blade/Pneumatocyst/Stipe Juice Extract

- - X X X X X X


347174-92-9 √ √ X X √ X X


- - X X X X X X


- - X X X X X X


- √ X X X √ X X


223751-75-5 - √ X X X X X

66. Pelvetia Siliquosa Extract

- - X X X X X X


Ingredient CAS # InfoBase SciFinder PubMed TOXNET FDA EU ECHA IUCLID SIDS HPVIS NICNAS NTIS NTP WHO FAO FEMA Web 67. Phyllacantha Fibrosa

Extract - - X X X X X X

68. Rissoella Verruculosa Extract

- - X X X X X X


- - X X X X X X


- - X X X X X X


- - X X X X X X


- - X X X X X X


- - X X X X X X


- - X X X X X X


- - X X X X X X

76. Sargassum Horneri Extract

- - X X X X X X

77. Sargassum Muticum Extract

- - X X √ X X X


- - X X X X X X


- - X X √ X X X


- - X X X X X X

81. Sargassum Vulgare Extract

- - X X X X X X

82. Sahel Scenedesmus Extract

- - X X X X X X

83. Sphacelaria Scoparia Extract

- - X X X X X X


- - X X X X X X

85. Undaria Pinnatifida Extract

- - X √ X X X X

86. Undaria Pinnatifida Cell Culture Extract

- - X X X X X X


- - X X X X X X

88. Undaria Pinnatifida Powder

- √ X X X √ X X

89. Undaria Pinnatifida Root Powder

- √ X X X √ X X N N N


Botanical and/or Fragrance Websites (if applicable) Ingredient CAS # Dr. Duke’s Taxonomy GRIN Sigma-Aldrich IFRA RIFM

1. Agarum Cribrosum Extract

-

2. Alaria Esculenta Extract -

3. Ascophyllum Nodosum - 4. Ascophyllum Nodosum

Extract -


84775-78-0

6. Asterionellopsis Glacialis Extract

-


-


-

9. Cystoseira Amentacea/Caespitosa/ Branchycarpa Extract

-


-


-


-


-


-


-


-


-

18. Dictyota Coriacea Extract -

19. Durvillea Antarctica Extract

-

20. Ecklonia Cava Extract -


Ingredient CAS # Dr. Duke’s Taxonomy GRIN Sigma-Aldrich IFRA RIFM 21. Ecklonia Cava Water -

22. Ecklonia Kurome Extract -

23. Ecklonia Kurome Powder -


-

25. Ecklonia Maxima Extract -

26. Ecklonia Maxima Powder -

27. Ecklonia Radiata Extract -

28. Eisenia Arborea Extract -

29. Fucus Serratus Extract 94167-02-9 30. Fucus Spiralis Extract -

31. Fucus Vesiculosus -

32. Fucus Vesiculosus Extract

-

33. Fucus Vesiculosus Powder

-


-


-

36. Himanthalia Elongata Extract

-


- X X X X X X

38. Hizikia Fusiforme Extract -

39. Hizikia Fusiformis Water -


-


-


84696-13-9


-


Ingredient CAS # Dr. Duke’s Taxonomy GRIN Sigma-Aldrich IFRA RIFM 44. Kappaphycus Alvarezii

Extract 1220882-72-4

(generic)

45. Laminaria Angustata Extract (Retired)

-

46. Laminaria Cloustoni Extract

90046-11-0

92128-82-0


-

48. Laminaria Digitata Extract

90046-12-1

92128-82-0

49. Laminaria Digitata Powder

-

50. Laminaria Hyperborea Extract

90046-13-2

92128-82-0

51. Laminaria Japonica Extract

92128-82-0


-

53. Laminaria Longissima Extract

-


-


92128-82-0


90046-14-3

92128-82-0


-


-

59. Macrocystis Pyrifera (Kelp)

-


-


347174-92-9


-


-


Ingredient CAS # Dr. Duke’s Taxonomy GRIN Sigma-Aldrich IFRA RIFM 64. Nereocystis Luetkeana

Extract -


223751-75-5

66. Pelvetia Siliquosa Extract -

67. Phyllacantha Fibrosa Extract

-

68. Rissoella Verruculosa Extract

-


-


-


-


-


-


-


-


-

77. Sargassum Muticum Extract

-


-


-


-

81. Sargassum Vulgare Extract

-

82. Sahel Scenedesmus Extract

-

83. Sphacelaria Scoparia Extract

-


-


Ingredient CAS # Dr. Duke’s Taxonomy GRIN Sigma-Aldrich IFRA RIFM 85. Undaria Pinnatifida

Extract -


-


-

88. Undaria Pinnatifida Powder

-


-

Search Strategy [document search strategy used for SciFinder, PubMed, and Toxnet] SciFinder INCI names and CAS No. Ascophyllum Nodosum – 33 substance hits; 0 useful Ascophyllum Nodosum Extract – 1 substance hits; 0 useful Ascophyllum Nodosum Powder – 1 substance hit; 0 useful Fucus Serratus Extract – 1 substance hit; 0 useful Fucus Spiralis Extract – 1 substance hit; 0 useful Hydrolyzed Fucus Vesiculosus Extract – 1 substance hit; 0 useful Kappaphycus Alvarezii Extract – 1 substance hit; 0 useful Laminaria Cloustoni Extract – 2 substance hits; 0 useful Laminaria Digitata Extract – 2 substance hits; 0 useful Laminaria Hyperborea Extract – 2 substance hits; 0 useful Laminaria Japonica Extract – 1 substance hit; 0 useful Laminaria Saccharina Extract – 2 substance hits; 0 useful Laminaria Ochroleuca Extract – 1 substance hit; 0 useful Macrocystis Pyrifera – 79 substance hits; 0 useful Macrocystis Pyrifera (Kelp) Extract – 1 substance hit; 0 useful Pelvetia Canaliculata Extract – 1 substance hit; 0 useful Saccharina Angustata Extract – 1 substance hit; 0 useful PubMed (((((((((((((((Agarum Cribrosum Extract) OR Alaria Esculenta Extract) OR Ascophyllum Nodosum) OR Ascophyllum Nodosum Extract) OR Ascophyllum Nodosum Powder) OR Asterionellopsis Glacialis Extract) OR Cystoseira Tamariscifolia Extract) OR Cladosiphon Novae-Caledoniae Extract) OR Cladosiphon Okamuranus Extract) OR Cystoseira Amentacea/Caespitosa/ Branchycarpa Extract) OR Cystoseira Baccata Extract) OR Cystoseira Balearica Extract) OR Cystoseira Caespitosa Extract) OR Cystoseira Compressa Extract) OR Cystoseira Compressa Powder) OR 84775-78-0 AND (tox[sb]) = 55 hits, 5 possibly useful. (((((((((((((((Cystoseira Tamariscifolia Extract) OR Dictyopteris Membranacea Extract) OR Dictyopteris Polypodioides Extract) OR Dictyota Coriacea Extract) OR Durvillea Antarctica Extract) OR Ecklonia Cava Extract) OR Ecklonia Cava Water) OR Ecklonia Kurome Extract) OR Ecklonia Kurome Powder) OR Ecklonia/Laminaria Extract) OR Ecklonia Maxima Extract) OR Ecklonia Maxima Powder) OR Ecklonia Radiata Extract) OR Eisenia Arborea Extract) OR Fucus Serratus Extract) OR 94167-02-9 AND (tox[sb]) = 41 hits, 4 possibly useful.


(((((((((((((((Fucus Spiralis Extract) OR Fucus Vesiculosus) OR Fucus Vesiculosus Extract) OR Fucus Vesiculosus Powder) OR Halidrys Siliquosa Extract) OR Halopteris Scoparia Extract) OR Himanthalia Elongata Extract) OR Himanthalia Elongata Powder) OR Hizikia Fusiforme Extract) OR Hizikia Fusiformis Water) OR Hizikia Fusiformis Callus Culture Extract) OR Hydrolyzed Ecklonia Cava Extract) OR Hydrolyzed Fucus Vesiculosus Extract) OR 84696-13-9) OR Hydrolyzed Fucus Vesiculosus Protein) OR Kappaphycus Alvarezii Extract OR 1220882-73-4) AND (tox[sb]) = 231 hits, 4 possibly useful. (((((((((((((((Laminaria Angustata Extract) OR Laminaria Cloustoni Extract) OR 90046-11-0) OR 92128-82-0) OR Laminaria Diabolica Extract) OR Laminaria Digitata Extract) OR Laminaria Digitata Powder) OR 90046-12-1) OR 92128-82-0) OR Laminaria Hyperborea Extract) OR 90046-13-2) OR 92128-82-0) OR Laminaria Japonica Extract) OR 92128-82-0) OR Laminaria Japonica Powder) OR Laminaria Longissima Extract) OR Laminaria Ochotensis Extract) AND (tox[sb]) = 31 hits, 1 possibly useful. (((((((((((((((Laminaria Ochroleuca Extract) OR Laminaria Saccharina Extract) OR Lessonia Nigrescens Extract) OR Lessonia Nigrescens Powder) OR Macrocystis Pyrifera) OR kelp) OR Macrocystis Pyrifera (Kelp) Blade/Pneumatocyst/Stipe Juice Extract) OR Macrocystis Pyrifera (Kelp) Extract) OR Macrocystis Pyrifera (Kelp) Juice) OR Macrocystis Pyrifera (Kelp) Protein) OR Nereocystis Luetkeana Extract) OR 92128-82-0) OR 90046-14-3) OR 92128-82-0) OR 347174-92-9) OR 223751-75-5 AND (tox[sb]) = 1 hit, not useful

(((((((((((((((Pelvetia Canaliculata Extract) OR 223751-75-5) OR Pelvetia Siliquosa Extract) OR Phyllacantha Fibrosa Extract) OR Rissoella Verruculosa Extract) OR Saccharina Angustata Extract) OR Saccharina Japonica Extract) OR Saccharina Longicruris Extract) OR Sargassum Filipendula Extract) OR Sargassum Fulvellum Extract) OR Sargassum Fusiforme Extract) OR Sargassum Glaucescens Extract) OR Sargassum Horneri Extract) OR Sargassum Muticum Extract) OR Sargassum Pallidum Extract) OR Sargassum Siliquastrum Extract AND (tox[sb]) 40 hits, 5 possibly useful

((((((((((Sargassum Thunbergii Extract) OR Sargassum Vulgare Extract) OR Sahel Scenedesmus Extract) OR Sphacelaria Scoparia Extract) OR Undaria Peterseniana Extract) OR Undaria Pinnatifida Extract) OR Undaria Pinnatifida Cell Culture Extract) OR Undaria Pinnatifida Leaf/Stem Extract) OR Undaria Pinnatifida Powder) OR Undaria Pinnatifida Root Powder) AND (tox[sb]) = 21 hits, 3 possibly useful

LINKS

InfoBase (self-reminder that this info has been accessed; not a public website) - http://www.personalcarecouncil.org/science-safety/line-infobase ScfFinder (usually a combined search for all ingredients in report; list # of this/# useful) - https://scifinder.cas.org/scifinder PubMed (usually a combined search for all ingredients in report; list # of this/# useful) - http://www.ncbi.nlm.nih.gov/pubmed Toxnet databases (usually a combined search for all ingredients in report; list # of this/# useful) – https://toxnet.nlm.nih.gov/ (includes Toxline; HSDB; ChemIDPlus; DAR; IRIS; CCRIS; CPDB; GENE-TOX) FDA databases – http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm (CFR); then, list of all databases: http://www.fda.gov/ForIndustry/FDABasicsforIndustry/ucm234631.htm; then, http://www.accessdata.fda.gov/scripts/fcn/fcnnavigation.cfm?rpt=eafuslisting&displayall=true (EAFUS); http://www.fda.gov/food/ingredientspackaginglabeling/gras/default.htm (GRAS); http://www.fda.gov/food/ingredientspackaginglabeling/gras/scogs/ucm2006852.htm (SCOGS database); http://www.accessdata.fda.gov/scripts/fdcc/?set=IndirectAdditives (indirect food additives list); http://www.fda.gov/Drugs/InformationOnDrugs/default.htm (drug approvals and database); http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM135688.pdf (OTC ingredient list); http://www.accessdata.fda.gov/scripts/cder/iig/ (inactive ingredients approved for drugs)


http://www.personalcarecouncil.org/science-safety/line-infobase

https://scifinder.cas.org/scifinder

http://www.ncbi.nlm.nih.gov/pubmed

https://toxnet.nlm.nih.gov/

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm

http://www.fda.gov/ForIndustry/FDABasicsforIndustry/ucm234631.htm

http://www.accessdata.fda.gov/scripts/fcn/fcnnavigation.cfm?rpt=eafuslisting&displayall=true

http://www.fda.gov/food/ingredientspackaginglabeling/gras/default.htm

http://www.fda.gov/food/ingredientspackaginglabeling/gras/scogs/ucm2006852.htm

http://www.accessdata.fda.gov/scripts/fdcc/?set=IndirectAdditives

http://www.fda.gov/Drugs/InformationOnDrugs/default.htm

http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM135688.pdf

http://www.accessdata.fda.gov/scripts/cder/iig/

EU (European Union); check CosIng (cosmetic ingredient database) for restrictions and SCCS (Scientific Committee for Consumer Safety) opinions - http://ec.europa.eu/growth/tools-databases/cosing/ ECHA (European Chemicals Agency – REACH dossiers) – http://echa.europa.eu/information-on-chemicals;jsessionid=A978100B4E4CC39C78C93A851EB3E3C7.live1 IUCLID (International Uniform Chemical Information Database) - https://iuclid6.echa.europa.eu/search OECD SIDS documents (Organisation for Economic Co-operation and Development Screening Info Data Sets)- http://webnet.oecd.org/hpv/ui/Search.aspx HPVIS (EPA High-Production Volume Info Systems) - https://ofmext.epa.gov/hpvis/HPVISlogon https://java.epa.gov/oppt_chemical_search/ https://java.epa.gov/oppt_chemical_search/ NICNAS (Australian National Industrial Chemical Notification and Assessment Scheme)- https://www.nicnas.gov.au/ NTIS (National Technical Information Service) - http://www.ntis.gov/ NTP (National Toxicology Program ) - http://ntp.niehs.nih.gov/ WHO (World Health Organization) technical reports - http://www.who.int/biologicals/technical_report_series/en/ FAO (Food and Agriculture Organization of the United Nations) - http://www.fao.org/food/food-safety-quality/scientific-advice/jecfa/jecfa-additives/en/ (FAO); FEMA (Flavor & Extract Manufacturers Association) - http://www.femaflavor.org/search/apachesolr_search/ Web – perform general search; may find technical data sheets, published reports, etc Botanical Websites, if applicable Dr. Duke’s https://phytochem.nal.usda.gov/phytochem/search Taxonomy database - http://www.ncbi.nlm.nih.gov/taxonomy GRIN (U.S. National Plant Germplasm System) - https://npgsweb.ars-grin.gov/gringlobal/taxon/taxonomysimple.aspx Sigma Aldrich plant profiler http://www.sigmaaldrich.com/life-science/nutrition-research/learning-center/plant-profiler.html Fragrance Websites, if applicable IFRA (International Fragrance Association) – http://www.ifraorg.org/ the Research Institute for Fragrance Materials (RIFM) should be contacted


http://ec.europa.eu/growth/tools-databases/cosing/

http://echa.europa.eu/information-on-chemicals;jsessionid=A978100B4E4CC39C78C93A851EB3E3C7.live1

https://iuclid6.echa.europa.eu/search

http://webnet.oecd.org/hpv/ui/Search.aspx

https://ofmext.epa.gov/hpvis/HPVISlogon

https://java.epa.gov/oppt_chemical_search/

https://java.epa.gov/oppt_chemical_search/

https://www.nicnas.gov.au/

http://www.ntis.gov/

http://ntp.niehs.nih.gov/

http://www.who.int/biologicals/technical_report_series/en/

http://www.fao.org/food/food-safety-quality/scientific-advice/jecfa/jecfa-additives/en/

http://www.femaflavor.org/search/apachesolr_search/

https://phytochem.nal.usda.gov/phytochem/search

http://www.ncbi.nlm.nih.gov/taxonomy

https://npgsweb.ars-grin.gov/gringlobal/taxon/taxonomysimple.aspx

http://www.sigmaaldrich.com/life-science/nutrition-research/learning-center/plant-profiler.html

http://www.ifraorg.org/

Brown Algae Minutes

September 2018 Meeting

Day 1 – Group 1

DR. MARKS: This is a first review of these 83 ingredients. They’re complex if I interpreted Dr.

Lowe’s presentation, which was excellent from two years ago, I guess. On page 156, they are a functional group of

plants and protozoa and unique organisms. They don’t fit real nicely into one little bundle.

I think we’re going to have to clarify whether all 83 in this report are seaweed kelp brown algae,

or whether there’s a unique brown algae in this, or there’s protozoa. As with all of these botanicals -- and this even

more, I think, complex chemistry and composition -- they vary in their composition levels depending on the species.

We have 83 here, no small number. How they were grown, where they’re harvested, what sea

they were grown in, how they were manufactured. They’ve been contaminated with heavy metals, specifically

arsenic. We eat them, so at least some of them are grass.

And so that leads to my first question. Tom and Rons, do you like all 83? Are there ones we

should eliminate, and if we do I’d like to know why. But presumably, the only reason you eliminate it is, it isn’t a

brown algae. I assume these are all brown algae.

DR. HELDRETH: Yes. Our understanding from the presentation that Dr. Lowe gave was we

arranged those that he determined brown algae. Then we also sent a message to the INCI nomenclature committee,

who has a biologist who’s an expert in the taxonomy of these types of things to give us an analysis. And to our best

understanding, all of the ingredients in this report are along the lines of a kelp or seaweed-type of brown algae.

DR. MARKS: I think that’s really important to capture. And I will, in the introduction, indicate -

- or somewhere that these are all brown algae, and they’re all seaweed, basically. Okay. Tom, Ron and Ron, go

back to the question, is there any reason to eliminate any one of these?

DR. HILL: I have a question. Do we have any sort of a phylogenetic tree that fits these algae? I

mean, because otherwise we’re looking at -- is there a group of deciduous trees, or something, which may be closely

related or not very closely related. I’m not sure how much read across one can do from one species to the next,

perhaps none. But if I know that two are closely related, that’s a start.

DR. HELDRETH: It was Dr. Lowe’s assertion that these were related.

DR. HILL: Well, I know they’re all brown algae; but again, I mean, that’s like saying all


flowering plants. That’s about as close as that gets me, I believe.

DR. HELDRETH: From Dr. Lowe’s explanation, it wasn’t really just based on whether or not

they were the color brown.

DR. HILL: Yeah. I know that.

DR. HELDRETH: It was a classification of a specific kelp-type of algae that excluded things

like, you know, little bacteria or other things that get classified in the very vague name algae. And he suggested not

only based on the similarities within the brown group, but how they’re often used in things like food and stuff that

these ingredients were similar enough to be group.

DR. HILL: Okay. But I still wonder if it’s possible to get a phylogenetic tree.

DR. EISENMANN: She did. If you look at Table 4.

DR. HILL: Okay. That’s effective, what she’s got?

DR. EISENMANN: It does break it down into subclass or family. There’s actually three -- or

four. And this is from a website, algae database. You can tell that some are more related than others.

DR. HILL: Right. I’m a visual learner guy. Like, you know, when you get a phylogenetic tree

it’s very pictorially useful. But, I mean, that’s a lot to ask. If there’s not one commercially available, which there

probably isn’t, but maybe there is, that would be helpful.

DR. MARKS: I guess when -- let’s see, it was Dr. Row, correct?

DR. SHANK: Lowe.

DR. MARKS: Lowe. His presentation, he says we employ four main criteria, pigmentation,

obviously, that’s the brown. Storage products. I assume we’re going to get that from composition. And we’re

going to read across -- hopefully we’ll get multiple compositions so that we can read across. On flagella, I don’t

think we’re worried about that in this case.

I’m looking on page 165 is where he talks about algal divisions, Ron Hill. And then if you go

right before that on page 163, I liked how that figure was labeled. Hypothetical. That doesn’t help much, does it?

And they have those nice little arrows going into different divisions and whatever.

DR. HILL: I have a colleague that works on algae symbionts in the context of natural products.

And basically, he sends them off now to get genetic profiling at Aberdeen so that we have a better idea than just

that. I do remember this slide because it’s very colorful.


DR. MARKS: I think we’ve settled on all the ingredients are okay, unless we hear differently.

DR. SHANK: Okay to be, inserted better.

DR. MARKS: Included. I’m sorry. Included in this report.

DR. SLAGA: Yes.

DR. MARKS: Yes. Exactly. I’m sorry. I didn’t get into what are the needs yet. Yeah, I have

some needs too also. Okay. They are glass, but how many of these specific species are grass? Or is that just kelp

that’s grass?

DR. SLAGA: A lot of them are kelp.

DR. MARKS: Yeah. But if you use the word kelp, is that inclusive of all? I don’t know. Ron

Shank, Ron is now getting down to the meat of this.

DR. SHANK: Well, the grass ones are Laminaria and Undaria. And from the page where all

these ingredients are numbered, the Laminaria are number 44 to 55. And the Undaria are numbers 81 to 86. And

these are grass food additives. I’d say all we need is skin sensitization. There’s also grass for Hizikia, numbers 37

to 39, but they’re not currently used. If they were used, we’d have to have skin sensitization data.

Then in Wave 2 we did get some skin sensitization on some, but not many. For all the rest, I

would say we need a 28 dermal toxicity study. And a skin sensitization study for all the extracts, at least. Assuming

that the extracts contain the components in the other preparations, which is a huge assumption I think. I don’t know

if that helps, but that’s where I come from.

DR. MARKS: I think it’s a really good start, because it gives us some framework. You’re really

focusing initially on the grass --

DR. SHANK: The grass ingredients.

DR. MARKS: -- grass brown algae. And that -- again, I’ll summarize this in a minute, make sure

I have the right numbers. But I like that. I can tell you with the skin sensitization, you were mentioning that, Ron. I

took the ones with the highest uses. Like the fucus vesiculosus extract, 6 percent.

Wave 3 had a mixture and an HRIPT, but I didn’t see that the percentage of that brown algae in

the mixture was mentioned. Was it? Did I overlook that? Because then I couldn’t -- if I knew it was 6 percent, I’d

say fine, that looks okay. The same you’d talked about the Laminaria that all we really need is the skin

sensitization. In Wave 3 we got another HRIPT. That’s of the extract, but it didn’t tell me what the percentage was.


Is that correct?

MS. CHERIAN: That’s the percentage that wasn’t mentioned in there.

DR. MARKS: No. Neither one of them. I would say I’d want --

DR. EISENMANN: All the ones from BiotechMarine did give concentration in the extract.

They gave it kind of as a range, the dry extract is, and they tested it neat. Most of that material was either in glycol

water or caprylic/capric triglyceride. There was a few propylene glycol extract.

Their information did give -- I mean, occasionally I had to go back and ask them for it, and that’s

written on each thing by hand. Then there was another table from a different company, and they were reluctant to

give concentration. They just said it was in the range of .5 to 10 percent for all of them on that one table, which was

less than desirable.

But from all the information from BiotechMarine, they did -- and it’s not in all of the summaries

that are for Wave 2, but it’s all --

DR. MARKS: We’ll need to go back and get that.

DR. EISENMANN: Right.

DR. MARKS: Because if that’s the case, and if it’s up to 10 percent -- the one was 6 percent for

the fucus extract. The Laminaria digitata extract, 5 percent. If they were tested up to 10 percent, then that becomes

a nonissue. Because the HRIPT’s were normal.

DR. EISENMANN: I don’t know if they ever have that high of concentration of an extract, that

company don’t. I’d have to look back. But they all say how much -- they don’t give exact, but they give a

reasonable sized range. Not like the other summary that came in, that is for all of the extract was .5 to 10 percent.

Not helpful.

DR. MARKS: We still need to be sure of what the percentage of the extract was in these

HRIPTs. We can’t say it’s safe if I don’t know the percentage. It gets back to, Ron, your question. The other was

Laminaria again and other grass group. Digitata powder, that was up to 40 percent in a leave-on. We need to have

sensitization on that.

And then I was picking just the ones with a high either use or concentration. Macrocystis pyrifera

kelp extract is used up to 36 percent, so I want to see sensitization on that. Yeah, I had an IDA. I figured we’d get

to an insufficient data announcement. Now the question is which ones.


That’s the initial sensitization but, Ron, I’m going to go back on what you said because I gave

specific species. But you were more general in terms of groups that we needed, which is good.

DR. SHANK: To start off, yes.

DR. MARKS: And then you had the 28-day tox also on the others. Then really, what is it,

Undaria, is that what it is?

DR. SHANK: Undaria.

DR. MARKS: Undaria species. Again, you felt just the sensitization data on them. And I would

think if we used the same reasoning we’ve done in the past, we really wanted -- most of these are extracts anyway.

But if we get the extract, presumably it would be a concentrated form of the contents or ingredients. Ron Hill, yeah?

DR. HILL: Well, just with the caveat that it may depend on what -- the trouble is when you get a

percentage added to a formulation and it’s so much percent of the extract, is that a .1 percent extract of what you’re

adding at 5 percent?

DR. MARKS: That was the problem I had with these. I couldn’t decide, on Wave 3, how much

of the actual brown algae percentage was in that testing, because it was X percentage of a mixture.

DR. HILL: And so, lacking that information, I don’t know how you --

DR. MARKS: That’s one of the data we’ll request. Okay. I like the way Ron divided things up,

Ron Shank. Shall we start with that in terms of that’s the way we would start with this large group of ingredients?

And then we’ll see how the approach from the other team is. And then as time goes on, we’ll even be more focused.

DR. BERGFELD: Can I ask Ron a question? Ron Shank? When you have grass ingredients and

people ingest all these, at what concentrations, are they 100 percent?

DR. SHANK: Usually they don’t -- you know, grass usually don’t give a concentration.

DR. BERGFELD: Is it the whole though? Whatever it is, the whole algae, they’re just eating

that?

DR. SHANK: Oh no, that’s defined. But how much is used in individual products usually isn’t

stated as far as I remember.

DR. KATZ: They usually don’t state it; although there may be some exceptions, but they usually

don’t. And I think it’s important, as I mentioned before, when you’re talking about grass, please make sure that you

say grass as related to food additives, so that it’s clear that it’s not grass as related to a cosmetic ingredient.


DR. BERGFELD: Do you think it would be worthwhile exploring what the grass food additives

have actually done? And in any way they might have talked about mixtures or full, just consumption of the actual

algae. I mean, with all these vegetarians and funny eaters, I mean, they may be ingesting 100 percent of a product,

of food stuff.

DR. SHANK: Very good question. In the literature search, were there FDA files that listed the

grass ingredients and what data were supplied to show it was grass?

MS. CHERIAN: I’m not sure. I didn’t do that part, but I can go back and check.

DR. SHANK: Okay. Because my experience with it is a lot of it is just a number of scientists,

and researchers, responded to FDA and said, this has been used widespread for a long time and it’s generally

recognized as safe. But there isn’t a huge database to confirm the safety. That’s my recollection.

DR. BERGFELD: Jim, one of the audience wants to.

DR. MARKS: Oh, I’m sorry. Thank you. Come on right up to one of the microphones so we

capture it. Thank you. Thanks, Wilma. I was trying to capture Ron’s divisions.

DR. ZIMMERMAN: Merle Zimmerman, American Herbal Products Association. A bunch of

these brown algae that are identified are in wide used as food ingredients. I know I eat at least two of the species in

this list with my lunch at the sushi bar on Monday. That might also be a relevant piece of information for purposes

of exposure and safety.

DR. SHANK: Yes.

DR. ZIMMERMAN: I can do some searches. If you’d like me to bring some stuff back, let me

know.

DR. BERGFELD: That really would be great. Because as I’m listening to all of this, and the

need for sensitization, if you could establish sort of the amount that’s ingested in historical review, we might be able

to come up with not such a great need for sensitization. Because we know about nickel. If you’re sensitized to

nickel, if you eat it, you break out, if nickel is incorporated in any of the food stuff.

DR. MARKS: I would still want to see their local lymph node assay, just to get an idea of is it a

sensitizer or not. Then either getting pig max or more importantly an HRIPT. I wouldn’t assume just because we

eat it and we don’t break out in a rash, that if we put it on topically, we would be okay. I’d like to see the skin

sensitivity. As far as the 28-day tox, if you can tell Dr. Shank what you’re eating of those other ones today, and if


you come back tomorrow, we you know it’s probably grass. That’s, of course, a joke. Ron, thank you for laughing.

Let me see if I have this right, Ron. I want to be sure. And if not, either I’ll -- I was thinking

about asking you to do your division, but I figured that would be it.

I’m going to second a motion tomorrow. I suspect it’s going to be an insufficient data

announcement. And with our discussions we took the Ron Shank approach. If you want, I can leave that out. That

the grass ingredients, and they were number 37 to 29, that’s the Hizikia species, the 44 to 55, the Laminaria species,

and the 81 to 86, the Undaria species, we need sensitization data. For the rest of the ingredients we need 28-day tox

and sensitization.

DR. SHANK: Those numbers that I used come from the table that begins on page 12 and list all

86. And each one is numbered.

DR. MARKS: Is this one that is from the -- let me see here. The table I’m using is this one here

that gives you what tests have been done.

DR. SHANK: Are they numbered?

DR. MARKS: And it’s numbered 1 through --

DR. SHANK: Eighty-six.

DR. MARKS: Is it 86? I said 83, I thought.

DR. EISENMANN: There’s a few that have been taken off of that table because they weren’t

actually brown.

DR. MARKS: Okay, that’s why.

DR. EISENMANN: Because I think the actual number is 82.

DR. MARKS: Oh, now it’s 82.

DR. SHANK: Okay.

DR. EISENMANN: I keep trying to find the 83rdd ingredient and I haven’t found it. If you find

me an 83rd ingredient, I’ll put it in.

DR. MARKS: Can we have an auctioneer here as far as how many ingredients?

DR. KATZ: Do you know which three or four should be removed?

DR. MARKS: Well, that can be clarified in the next rendition, I think.

DR. SHANK: The table on 12 goes to 89, one through 89.


DR. HILL: There’s two tables and they both go to 89.

DR. MARKS: Oh yeah, there’s Wave 3 again. Do you have the Wave 3 table where -- in

multicolor?

DR. SHANK: No. This is in the original document.

DR. MARKS: Okay. I think I had that one here. Does that corresponds? It’s the Hizikia, 37 to

39. There’s Hizikia extract, water and callus culture extract. Are those the three that -- I think I heard you right, 37

to 39, Ron?

DR. SHANK: Yes. That’s what I said. Actually, it looks like -- well, unfortunately it’s which

table you use.

DR. MARKS: Okay.

DR. SHANK: It’s the Hizikias. And in the very first table we got, that would be 38 to 40. But in

the other table it’s 37 to 39.

DR. MARKS: Well, maybe what I should do is just put -- rather than the numbers, put --

DR. SHANK: The actual names.

DR. MARKS: Yeah. I have the names in parentheses.

DR. SHANK: Okay.

DR. MARKS: I thought this was the original one. This isn’t? Again, I think we got three

different tables. Because the last one was the one that had the multicolor original submission, Wave 2 and Wave 3,

in red and blue. Maybe I’ll use that one. Let me see what number Hizikia is there. Thirty-seven, 38, 39. It’s again

37 to 39. Okay. And then the next ones are the Laminaria group. And I’ll say approximately 44 through 55.

DR. SHANK: Yes.

DR. MARKS: Okay. And then the last group of the grass kelp is 81 to 86, the Undaria species.

And I assume these are all species, right? I’m correct in saying species?

DR. EISENMANN: Mm-hmm.

DR. MARKS: Okay. And we need the sensitization and actually, specifically, I mentioned some

other ones where we need -- because of either the frequent use or the high concentration -- individual I put down

there. And then for the rest of the ingredients, we need a 28-day tox since they’re not grass. And then we also need

sensitization for them.


That makes it actually pretty straight forward at this point. We’ll see how complex the Belsito

team makes it. But does that sound good? This is actually going a little more -- thank you, Ron, for suggesting that

way of approaching it.

DR. SHANK: Okay.

DR. MARKS: Any other comments? Tom?

DR. SLAGA: No.

DR. MARKS: Ron Hill? We’re obviously going to see it again, particularly if it goes out as an

insufficient data announcement, which is hard for me to imagine it won’t. Priya, any questions?

MS. CHERIAN: No.

DR. MARKS: Any others from industry? Okay.

DR. SLAGA: It’s a very nice summary.

DR. MARKS: Oh, yeah.

DR. SLAGA: That helped a lot.

DR. MARKS: Okay. Thanks, Priya. Let’s go ahead and with that we will move on to hydrogen

peroxide, one of our favorite disinfectants.

Day 1 – Group 2

DR. BELSITO: Oh my God.

DR. LIEBLER: Kelp.

DR. BELSITO: Wave 2. Now here -- we’re getting Wave 4.

DR. LIEBLER: Wave 4 is just the greatest hits of Waves 2 and 3.

MS. CHERIAN: It’s just a summarization of the sensitization and dermal to make it easier.

DR. BELSITO: Okay. Well, we definitely need to limit arsenic. We need limits on heavy

metals. What about these extractions? Methanol, hexane, chloroform?

DR. LIEBLER: You know, so I thought we actually had a lot of information about the different

prep methods, and they seem to me to fall into a couple of categories. Maybe two or three categories to get these

ground-up powders, to get these alcohol extractions or these aqueous extracts.

And I wonder if it might not be possible to prepare a kind of a map diagram that just shows the


major ways in which brown algae is converted to cosmetic products. Maybe not so much with a high level of detail

in the map, but under method of manufacture it could be right there. I would imagine maybe sort of an inverted

pitchfork trident thing, you know, with three pathways. Because then you’d have a table with lots of information for

the individual ingredients.

MS. CHERIAN: Okay.

DR. BELSITO: Okay. Now, we know a lot about the impurities, we know a lot about the

method of manufacture, we know zilch about composition.

DR. LIEBLER: Yeah. I had a more specific question about composition, which was do we --

because of Wave 2, we now have data on the actual cosmetic ingredients, not just on some representative algae from

the literature.

DR. BELSITO: Right.

DR. LIEBLER: So, that’s good. And I had a question about constituents of concern with respect

to sensitization for example. And we don’t have data on those for any representative, at least -- I might have missed

it in the blizzard of Wave 2 or Wave 3.

DR. BELSITO: Well first of all, the two biggies are Laminaria digitata and macrocystis. Those

are the ones that are most frequently used, right?

MS. CHERIAN: Yes.

DR. BELSITO: And we have an HRIPT on 46 humans for laminaria, but we have no data for

macrocystis.

MS. CHERIAN: We have some data for that ingredient --

DR. BELSITO: We have no sensitization data.

MS. CHERIAN: -- either in Wave 2 or 3.

DR. BELSITO: I didn’t see it.

MS. CHERIAN: Okay. Let’s see.

DR. BELSITO: And all of the times that these were irritant, it was always with propylene glycol.

And I thought propylene glycol was the irritant there. I was okay with the irritation, but we have no sensitization

data for macrocystis. And we have just an HRIPT on 46 individuals for laminaria.

And we also have no tox data for either one of them. And at most, we have 28-day tox data. And


that raises the whole issue of iodine concentration and thyroid effects.

DR. LIEBLER: You’re talking about macrocystis?

DR. BELSITO: Yeah. Now the thyroid issues with ingestion of these kelps were extremely high

amounts, but we don’t have absorption data. And then we don’t really have good genotox data. And then we have

some endocrine effects. We don’t have photo, we don’t have composition, we don’t have 28-day dermal absorption.

We don’t have sensitization on macrocystis, we don’t have photo. The genotox, there’s some report of endocrine

affects.

DR. LIEBLER: Yeah. I’m trying to get some idea of how widespread food consumption is with

the ones that we’re using. Macrocystis, laminaria digitata, laminaria saccharina approved as food additive or direct

food addition, food for human consumption as a source of iodine or as a dietary supplement. I don’t know to what

extent that factors into our need for dermal tox or additional tox data.

My hunch with these is that we may be treating these more the way we treat other kinds of

botanicals, where our major concerns is going to be sensitization and constituents of concern. Maybe that’s not

accurate, but that how I first approached these.

DR. KLAASSEN: Well, they are considered food additives, especially for animals to quite a

high extent, without apparent toxicity, which gives me some support.

DR. LIEBLER: In the acute oral toxicity study, it’s Table 21, PDF Page 55, we have a relatively

small selection of brown algae compounds that have been tested -- or brown algae that have been tested. For our

report, the fucus vesiculosus, there are three different studies in Swiss mice.

But if you look at all the brown algae that have been tested there’s, let’s see one, two, three, four,

five, six, seven, eight studies, all of which have oral LD50s in the thousands. These are sort of the profile of

nontoxic substances.

As far as dermal absorption, you know, it’s basically a botanical. So, it’s got sort of a wide variety

of chemical substances, many of which are not absorbed at all.

DR. BELSITO: But we don’t even know what they are.

DR. LIEBLER: That’s a concern I have is the chemical composition of these. But I would say,

particularly with respect to constituents of concern relative to sensitization. And of course, I didn’t realize that these

tended to accumulate arsenic so much.


DR. BELSITO: Right.

DR. LIEBLER: I found that interesting and surprising. Think of all the kelp in the world. This

could actually be a major reservoir of arsenic other than the earth’s crust.

DR. KLAASSEN: I think that arsenic form is not so toxic. It says in here some place that they’re

arsenic sugars. And I know at least fish, also, concentrate arsenic and puts it in a form that’s not toxic like the

inorganic form is. But I’m not entirely positive about this. But yeah, that’s kind of interesting.

DR. LIEBLER: Paul have comments?

DR. BELSITO: Brown algae. “Extracts to 36 percent. Powders to 40. Juices no concentration.

Water no concentration. Many uses with no concentration data provided. Plant-like, seaweed, protozoa, unique

kingdoms -- very diverse group, too diverse?? Impurities; phytosterols, alginic acid, heavy metals, especially,

arsenic, and phthalates. No data on composition. Tox data limited, but no level of toxicity. This one is touch with

such a diverse number of sources and ingredients; don’t know where to begin other than composition and impurity

data base on some sort of plausible grouping.” And that was my problem. We’re just sort of assuming these all

have the same composition.

DR. LIEBLER: Well, yeah. I mean, I suppose implicitly we’re assuming that they have similar

enough composition to be grouped together. If we did play the mental exercise of deciding to break these up, how

would we break them up?

DR. BELSITO: I don’t know.

DR. LIEBLER: With what would seem to be anything other than arbitrary.

DR. BELSITO: But wouldn’t it be nice if we had composition on a couple different -- like at

least the two that are primarily used for laminaria and the macrocystis?

DR. LIEBLER: Right. No, I agree. That’s one of the notes I had, is that we need data on

composition for the representative of the major groups. Particularly, I thought constituents of concern. Maybe

you’re not as concerned about sensitization with these, Don?

DR. BELSITO: I don’t know. I mean, that’s was one of my needs. I raised to you was an

HRIPT of 46 sufficient for the laminaria, but we have nothing on macrocystis, which is the other one that has a high

concentration of use.

DR. LIEBLER: I think we definitely need that. And I think of these as botanical. And with


botanicals, we almost always are looking for constituents of concern. Flavonoids, terpenoids, things like that. And

at least if we have representative data for the different classes, along with safety data on sensitization, then we can

draw a conclusion.

We don’t have genotox on major -- we have genotox on a couple of fucus vesiculosus?

DR. BELSITO: Mm-hmm.

DR. LIEBLER: But we don’t have it on any of the laminaria, do we?

DR. BELSITO: Nope.

DR. LIEBLER: Or the macrocystis?

DR. BELSITO: Nope.

DR. LIEBLER: I think we need that.

DR. HELDRETH: Is there one for laminaria saccharina extract? At least according to Priya’s

table, it looks like there’s genotox for Number 55.

DR. LIEBLER: I might have buzzed by it.

DR. BELSITO: The genotox is not on laminaria though.

DR. LIEBLER: We have laminaria digitata, prep method concentration not specified, AMES

assay with and without metabolic activation. There’s a reference, I didn’t look at it. Is that what you’re referring to,

Bart?

DR. HELDRETH: In Priya’s cheat sheet table here, number 55 in the table says laminaria

saccharina extract.

DR. LIEBLER: Oh, sorry.

MS. CHERIAN: Oh, it’s in Wave 2.

DR. HELDRETH: So, data came in Wave 2.

DR. LIEBLER: I think the other problem in reviewing this report is the data are spread out over

so many reports, that I just was missing stuff.

MS. CHERIAN: And I think fucus vesiculosus was the highest number of uses and

concentration. But the concentration might have gone down.

DR. LIEBLER: Okay, so the cheat sheet’s only for the skin endpoints, right?

DR. KLAASSEN: Right.



DR. LIEBLER: Yup.

DR. HELDRETH: No. It has repro, geno.

DR. KLAASSEN: Oh, he’s talking about the one she handed out 30 minutes ago.

MS. CHERIAN: That’s the data profile.

DR. HELDRETH: Yeah, the data profile.

MS. CHERIAN: Yeah. So, it’s not on there. The genotox data is not on there, it’s in Wave 2.

That’s only skin sensitization and irritation.

DR. LIEBLER: Alright. I think -- it’s hard to tell what we have at this point.

MS. CHERIAN: Yes. Yeah.

DR. BELSITO: But the genotox data is on laminaria saccharina and not digitata?

DR. HELDRETH: True.

DR. LIEBLER: And where are you getting that, Don?

DR. BELSITO: Wave 2.

DR. HELDRETH: So, on Page 6 of Wave 2, it says for laminaria saccharina extract, the genotox

says, tradename mixture containing this ingredient in seawater and methylpropanediol AMES test, salmonella

strains. It lists five of those with and without metabolic activation in dose 50 to 5000 micrograms per plate, non-

mutagenic.

DR. LIEBLER: Okay. But I think we need to have representative genotox for the major classes.

And it looks like we’ve got it for laminaria.

DR. BELSITO: But does that take care of laminaria digitata?

DR. LIEBLER: In addition to the Wave 2, there is what was in the report, Table 23, which said

laminaria digitata -- this is PDF 60 in the original report. And it’s an AMES assay with and without metabolic

activation. But it doesn’t specify concentrations.

DR. BELSITO: Right.

DR. LIEBLER: It’s probably not a great study. So, it’s thin and nonexistent for macrocystis.

DR. BELSITO: Right.

DR. LIEBLER: But we’ve got two fucus vesiculosus in the report, Table 23, with


concentrations. One is a common assay, which isn’t the best; it’s not very sensitive. And the other is the

chromosome aberration OECD GL 487. So, we really need more on fucus vesiculosus unless that’s in Wave 2.

MS. CHERIAN: There’s no genotox.

DR. LIEBLER: None?

MS. CHERIAN: For that ingredient, no.

DR. LIEBLER: Okay.

DR. BELSITO: Macrocystis.

DR. LIEBLER: Fucus I was talking about. And then macrocystis. So, we’re lacking genotox

for both of those. We don’t have any AMES for fucus.

MS. CHERIAN: No.

DR. LIEBLER: I mean, relatively to the number of ingredients is really spotty.

DR. BELSITO: Okay. So insufficient, is that fair to start with?

DR. LIEBLER: Yes. Right.

DR. BELSITO: Okay. And do we have enough on the residual impurities? Or do we just simply

say restrict arsenic, heavy metals and extraction solvents?

DR. LIEBLER: I think actually we’ve got a lot of data on the residual metal impurities, or

arsenic and metals. And we obviously should treat that in a discussion and say restrict. I’m more concerned about

the lack of data on the organic constituents of concern.

DR. BELSITO: What do you mean, the extractants?

DR. LIEBLER: No.

DR. BELSITO: The solvents?

DR. LIEBLER: Like terpenoids and flavonoids. Not the impurities, the constituents of concern

that could contribute to sensitization.

DR. BELSITO: Okay.

DR. LIEBLER: All the data we have so far are non-sensitizing?

MS. CHERIAN: Yes.

DR. KLAASSEN: It looks pretty clean.

DR. BELSITO: We don’t have a lot of sensitization data.


DR. LIEBLER: I mean, how comfortable are you with the sensitization?

DR. BELSITO: I don’t know what’s in them.

DR. LIEBLER: Well, okay. If you were concerned about sensitization with these, then that

increases the need for data on the constituents of concern that are associated with sensitization.

DR. BELSITO: Right.

DR. LIEBLER: If you had a very thorough list of studies that were to show non-sensitizing in

humans, at use concentrations, then I wouldn’t be so concerned about having data on terpenoids and flavonoids and

so forth.

DR. BELSITO: So, we need composition on laminaria and macrocystis?

DR. LIEBLER: Yes.

DR. BELSITO: We need a 28-day dermal? Or are you happy with a grass status?

DR. LIEBLER: I think the grass status helps. We’ve got Table 22, Oral repeated dose. We

hardly have any studies in which there’s evidence of toxicity, either in acute or repeat dose.

DR. BELSITO: (Inaudible) dose with the extract for iodine.

DR. LIEBLER: Yeah.

DR. BELSITO: Thyroid affects.

DR. LIEBLER: Right. I mean, because it’s such a big group, we don’t have a comprehensive

data set for toxicity with all of them. But for what we do, it’s a pretty consistent message; these aren’t really toxic.

DR. BELSITO: So, you don’t need a 28-day dermal?

DR. LIEBLER: I don’t think we need the 28-day dermal. If you take that information, plus the

widespread use of these as dietary supplements or food additives.

DR. BELSITO: Okay, so we’re not worried about dermal absorption because we have all of this

grass status, dietary supplement, et cetera.

DR. LIEBLER: Right.

DR. BELSITO: Okay. And then we need composition on laminaria, macrocystis, sensitization

and irritation and concentration of use for macrocystis. And we’re okay with the 46 for laminaria?

DR. LIEBLER: If you’re okay with it, I’m okay with it.

DR. BELSITO: Well, I guess we’ll see what the composition looks like. Photo absorption?


DR. LIEBLER: Photo absorption?

DR. BELSITO: Yeah.

DR. LIEBLER: Oh, I’m sure they all absorb. I mean, they’re complexed, you know, botanicals.

They all absorb.

DR. BELSITO: So, then we need photosensitization/photo-irritation?

DR. LIEBLER: I don’t think that necessarily follows. Do we have any photosensitization on

any of them?

DR. BELSITO: Nope.

DR. LIEBLER: I mean, complexed organic mixtures all absorb, but not all of the absorbing

materials -- I mean, most of the absorbing materials are not photo allergens or photosensitizers.

DR. BELSITO: Right. But some of them are.

DR. LIEBLER: I mean, with pure compounds, absorption tells you something.

DR. BELSITO: Right.

DR. LIEBLER: With mixtures, absorption doesn’t tell you anything. So, the kind of logic use in

RIFM where if it has absorption above or below the benchmark, clears it, that doesn’t apply in mixtures like this.

DR. BELSITO: Right. So how do we deal with that?

DR. LIEBLER: If we had --

DR. BELSITO: Composition.

DR. LIEBLER: -- composition. Again, constituents of concern, including known

photosensitizers. Flavonoid, terpenoid sensitizers. That’s why I kept coming back to that point. If those are low, or

minimal, or at least documented and the measured amounts are present in ingredients that have been tested, at least

for sensitization, then I think we’re okay.

For photo, that’s really hard to predict for mixtures. For pure compounds, sure. But for mixtures,

it’s really hard to predict. And then I don’t know that we’re going to get very far by saying we want

photosensitization on everything. I mean, we can ask for photosensitization on representative ingredients from the

major groups.

DR. BELSITO: So, photosensitization, phototoxicity for laminaria and macrocystis, or

concentration of use?


DR. LIEBLER: Yeah. And if we don’t get that and they respond with data on constituents,

particularly organic constituents that might be associated with photosensitization, then we can take that into

consideration.

DR. BELSITO: What about genotox?

DR. LIEBLER: Based on what I’ve seen so far, I think the data are thin. We’d like more

genotox data. Particularly for --

DR. BELSITO: For laminaria.

DR. LIEBLER: On the laminaria.

DR. BELSITO: On macrocystis.

DR. LIEBLER: Macrocystis, right. Yeah.

DR. BELSITO: Anything else? Developmental repro? No?

DR. LIEBLER: I really doubt it. I mean, I don’t think we’re going to need it.

DR. BELSITO: Are we clear on the genotox, on the idea that they’re used as foods?

DR. LIEBLER: What do we have on carcinogenesis?

DR. BELSITO: Nothing.

DR. LIEBLER: Nothing.

DR. KLAASSEN: Well, you know, this is our first time around. I think we should ask for

genotoxicity.

DR. LIEBLER: Yeah.

DR. BELSITO: Okay. For again, laminaria and macrocystis?

DR. KLAASSEN: Right.

DR. LIEBLER: I agree with you, Curt.

DR. KLAASSEN: And regarding phototoxicity, that’s -- you know, these chlorophyll-type

compounds and chlorophyll degradation products are photosensitizers. So therefore, to request those there is some

reason.

DR. LIEBLER: I think we agreed on that. I think we agreed we’re going to ask for that.

DR. KLAASSEN: But all I’m saying is it’s not just grabbing out of nothing. There’s a kind of a

reason for it.


DR. BELSITO: The list I have so far is we would like some information on the composition of

laminaria and macrocystis. Sensitization and irritation and concentration of use for macrocystis. Phototoxicity,

photosensitization at concentration of use for macrocystis and laminaria. And some genotox on laminaria and

macrocystis. That it?

DR. LIEBLER: Yes.

DR. BELSITO: Anything else?

DR. KLAASSEN: That should be good enough.

DR. BELSITO: Any other comments on brown algae? Okay.

DR. LIEBLER: I think this will be easier to deal with next time when we can have it all in one

document.

DR. KLAASSEN: Yeah.

DR. BELSITO: Oh, well, then we still get Wave 7 and 8. Okay.

Day 2

DR. BELSITO: Well, this is huge and I’m not going to read all of them, but the two major ones

laminaria digitate and macrocystis. And we thought we could use those as our sort of, for lack of a better word,

read across to brown algae.

We thought that there was a lot of data about impurities, but we don’t know what these are made

of. We don’t know composition. So, we’re asking for the composition on laminaria and macrocystis to see how

similar different types of brown algae were.

We do have sensitization and irritation on the laminaria, but not the macrocystis, and we’re asking

for that. And we’re asking for genotoxicity on the laminaria and the macrocystis extract, as insufficient data.

DR. BERGFELD: So, that’s a motion?

DR. BELSITO: That’s a motion.

DR. BERGFELD: Dr. Marks?

DR. MARKS: We second the insufficient data announcement. We, or I might say Ron Shank,

had a different approach which was appealing. Ron divided these -- what is it 83 ingredients -- into two groups, the

grass group and the non-grass group. And the grass group was, depending on which list -- I think we got three


different tables -- but the hizikia species, 37 to 39, at least, in the table I use, and the laminaria species 44 to 55

numbered, and then the undaria species, 81 to 86. We wanted the sensitization data on those. For the rest of the

ingredients, which were not grass ingredients, we wanted a 28-day tox and sensitization. We like, obviously, the

composition. I didn’t feel as comfortable with the sensitization data on several of the ingredients you mentioned.

In Wave 3 we did get HRIPT, which was good for the fucus vesiculosus, and the laminaria digitata

extract at 5 percent. But, in both of those, I wasn’t able to determine what the concentrations of those ingredients

were in that mixture. They just said the mixture was tested and the HRIPT was okay; but I didn’t know what

percentage of that mixture was the actual algae ingredient.

For the laminaria digitata powder, that’s being used at 40 percent, and I saw no evidence as far as

sensitization confirming its safety. And the macrocystis extract, that’s used at 36.4 percent and there was no data

on sensitization.

So, I think we can roll together what both teams need. Our team found it appealing the way Ron

Shank approached it. So, a lot of the toxicity data, such as the 28-day tox wouldn’t be necessary for the grass

ingredients of this large group.

DR. BERGFELD: Do you want to comment, Dan?

DR. LIEBLER: It actually disturbs me to realize I had the same idea as Ron Shank. But I’m

curious as to whether or not we can actually get a good inventory of the ingredients, in our report, that are

associated with grass for food enhancers and flavor adjuvants and so forth. So, can we get a good listing of that, do

we know?

DR. MARKS: Well, that could certainly be in the insufficient data announcement.

DR. SHANK: So, we know which are which. Because I like the idea -- I mean, I recognize as

well, all kidding aside, that many of these are widely consumed. And this could be very similar to some of our

other botanical ingredients where, like apple or orange or something, that, you know, they’re widely consumed and

we mostly focused on the skin endpoints.

So, I agree with that. And I just want to make sure that we can -- I’d like to know to the extent to

which we could get a good inventory, what is grass? What could be considered that way?

DR. BERGFELD: Linda, could you respond at all?

MS. KATZ: No, not really, because I don’t do grass, it’s not within my jurisdiction. I’m


presuming that you can always make a FOIA request and the FDA can provide that information; but it’s not

something from my group. One of the other groups, the Office of Food Additive Safety is the one who handles that

determination.

DR. BERGFELD: Thank you. Any other comments?

DR. MARKS: I think, as again as this moves forwards we need to really, in the introduction and

discussion, really emphasis how complex this is. And the algae that their definition, at least by Dr. Lowe’s

presentation, is that they’re functional groups and that they’re mixtures. I asked yesterday whether these are all

seaweeds, and it appears they are all seaweeds. They aren’t protozoa, or they aren’t some unique kingdom. So, I

think that’s important.

And then, obviously, we not only have the complexity of botanicals in terms of their chemistry

composition -- which we’re going to ask for the composition. But these composition levels varied depending on

species, varied on growing, harvesting, method of manufacture. And then, these particularly is concerned about

contamination by heavy metals and arsenic, and that all needs to be captured in the discussion.

DR. BERGFELD: I want to make one comment since there’s so much data here; that I

personally, as a Chair, would like the data profile updated with all the Wave information that came through.

DR. MARKS: Oh sure, we’ll see that in the next rendition.

DR. BERGFELD: Okay.

DR. SLAGA: That’ll be very helpful.

DR. BELSITO: Priya did a very good job of putting all of those sensitization and irritation data

together for us, so good work.

MS. CHERIAN: Thank you.

DR. MARKS: Yes, and method of manufacture and impurities. Each Wave came with another

two pages of tables, or three or four.

DR. LIEBLER: I had suggested a map. No, just a schematic, because it seemed like there were

some recurrent themes with a lot of little individual differences of the types of preparations that are made; sort of a

powder versus an alcoholic extract versus an aqueous extract, et cetera. And maybe like an upside down trident

that might have examples of some of the families and how they’re -- just to orient the reader into how these things

are turned from kelp, you know, algae to products that are more tangible. So, that’s what I suggested to Priya.


DR. MARKS: And we certainly divided the botanical as to safe and insufficient, depending on

whether the final product is an extract or a powder or a juice or whatever; so, that is important.

DR. BERGFELD: All right. I think that we’ve had enough discussion, then, to call to question.

All those in favor of the conclusion of insufficient data announcement? Thank you. Unanimous. Well, that was

quick. Thank you, Don, and thank you Jim. As I thought it would be longer. Let’s move on to the next ingredient,

the Acrylates Copolymers, Dr. Marks.

DR. HELDRETH: Before we move on, could we just get a reiteration of the needs, so that Priya

has everything she needs for the announcement.

DR. BERGFELD: Okay.

DR. BELSITO: Why don’t you go ahead Jim because you added some in. I’m fine adding as

many insufficiencies as we need at this point.

DR. MARKS: The first thing would be which one of these algae really are grass designated?

And then the second, we basically need sensitization for everything. But from the hizikia, the laminaria and the

undaria, we felt we had enough to move forward since these are grass ingredients that all we need was

sensitization. The rest of the ingredients we want the 28-day tox, along with sensitization -- and genotox.

And composition. Don, you had brought out a couple of lead ingredients for composition. As far

as I’m concerned, let’s get as much composition as we can get for as many different species of algae. But, Don,

you were specific in naming species.

DR. BELSITO: Well, most of them are very low concentration of use with the exception of the

laminaria digitata, which is at 50 percent. I’m sorry I made a mistake; I had written down that sensitization was at

50 percent propylene glycol, it’s 5. So, I guess we need sensitization for that as well.

And the macrocystis, which is at 33, I think, .4 percent in a leave-on. So, I just sort of saw those

as the two lead products. And if we can get composition on them, and seeing that the compositions of these algae

are pretty similar, we could use data from the read-across for those two that are used in very high amounts, to help

clear a lot of other information.

DR. MARKS: So, I think as much composition as we can get.

DR. BELSITO: But we have a lot of sensitization and irritation, as you can see, from the table

that Priya provided for us yesterday.


DR. MARKS: Yeah. Unfortunately, they weren’t in the ones that are most commonly used.

DR. BELSITO: Right.

DR. MARKS: And there were some big numbers of use. And that’s why you picked those out,

Don, I concur.

DR. BERGFELD: Are you okay with the needs assessment and what is needed?

MS. CHERIAN: Yes.

DR. BERGFELD: All right, we’ll move on then. We’re going on then, again, to the

Copolymers, Dr. Marks?

December 2018 Meeting

Group 1 – Day 1

DR. BELSITO: Okay, brown algae-derived ingredients. At the September meeting we issued an

insufficient data announcement for the 82 ingredients. And we wanted composition and organic constituent data for

each of these brown algae-derived cosmetic ingredients. Twenty-eight-day dermal toxicity for ingredients that are

not GRAS, sensitization data at relevant use concentrations for all ingredients, and genotoxicity data for those

ingredients that are not GRAS.

Since that time, we’ve gotten a bunch of data. Some of which we got in waves just before the

prior meeting, and it has now been incorporated into the report. And we have comments from the council. Then we

got another Wave 3, on brown algae, which looked at the Laminaria Digitata extract at 20 percent for sensitization.

However, it’s used at 40 percent. But it also turns out that the ones that have the highest concentration of use, the

Laminaria Digitata and the Macrocystis, are also GRAS substances.

Anyway, we certainly didn’t get nearly as much as the data that we asked for, since we’re asking

for, like, data on all of these ingredients, which we’re not going to get.

I, honestly, don’t quite know where to go. I mean, for me we asked for concentration of use, we

got 20 percent with the Laminaria. But when you sort of look at what these things are composed of, it’s not likely

that they’re going to be sensitizing. I think the biggest issue is the heavy arsenic and heavy metal composition for

them. But I’m just curious as to what the rest of my team thinks.

DR. LIEBLER: Well, I’m about where you are, Don. My overall comment on this group, is that

this is beginning to make sense. We have GRAS for several of the most used ingredients, tox data on a couple of the


non-GRAS ingredients, including the mucosa. And the overall tox and genotox profile on these are all clean.

I don’t know if the body of sensitization data is sufficient for you, so that was a question mark for

me. But I’m moving towards safe as used on these.

DR. BELSITO: I mean, when you look at what’s in them, it’s really pretty banal stuff. I’m not

seeing anything coming out of them, even like you would see in a botanical. There’s no fragrance-like ingredients,

there are no pinings. There are none of those things, comings out of these algae, that would sensitize from, at least,

the limited data that I see. And I don’t really believe that there’s going to be any difference, among any of these, in

terms of potential sensitizers.

DR. LIEBLER: We do have a growing assembly of information on constituents. And there’s

still more along the lines of chemical classifications. I’m scrolling up to the tables that have them. It’s better, it’s

still not ideal. I can’t say that we have data that shows that the flavonoids in these don’t include constituents of

concern.

So, that’s what I was looking for, or at least some kind of numbers on those. I don’t see those yet.

And I don’t know if anything is available. But on the other hand, the safety data that we have doesn’t give a whiff

of sensitization. And my main question was whether or not the concentrations tested were sufficient on

sensitization, Don. And you just pointed out we’re a little short of maximum use concentration.

DR. BELSITO: We clearly don’t have the data for Macrocystis. And for Laminaria, in the wave

we got, it was at 20 percent. But, I’m not seeing anything there that would be a sensitizer. I agree, the composition

data is somewhat limited. But when you look at it, I’m just not seeing anything that catches my eye as potentially

causing skin sensitization. Paul and Curt, what did you --

DR. EISENMANN: I still haven’t gotten the company, that's using that highest concentration, to

confirm or deny those high concentrations. I’m still working on them. I was hoping by now they would have given

me some kind of a response, but they haven’t yet.

DR. KLAASSEN: I guess maybe the greatest confidence, in regard to toxicity, is that some of

these are GRAS substances. I know that doesn’t cover the external effects on the skin, but again, there’s really no

indication that anything’s happening.

DR. SNYDER: I struggled with this group. It’s large, it’s complex. And every time you kind of

think you have some data that you maybe could use to read across, then you realize, well, is this really reading


across. But my overall sense was that the systemic toxicity issue, for the ones that we have data on, is very, very

low.

And so then I, by default, went to the sensitization. And again, it’s the same thing. We have some

sensitization data, it’s not at the concentration we’d like to have it at, it’s not with all the ingredients, but I think we

have a body of it -- as you said Don -- that there’s no reason to suggest that sensitization would be an issue with

these. Particularly, in light of the fact, as Curt said, many of these are GRAS; or there are no constituents of concern

that we have data to indicate would be of concern. Again, it’s difficult, but I think we’re there.

DR. LIEBLER: We have a large number of ingredients. And we have a relatively smaller

percentage of those that are actually used, must less heavily used. And of those, those are where all of our GRAS

ingredients are. But we have a couple of major ones in the heavily-used category. Like the fucosa that aren’t

GRAS, but we have tox data on those. And the tox data suggests that there’s no systemic toxicity potential for

these.

So, even though we don’t have data on even a plurality of the ingredients we’re looking at, we

have sufficient information, I think, on the ones with the highest uses and exposures, to make me feel confident in

moving towards a safe-as-used assessment on these.

DR. BERGFELD: How would you put that in your discussion to cover all of these ingredients?

DR. LIEBLER: It's hard. I don’t remember now. I’m scrolling down past the tables, which

fractions of these are not -- oh, no reported use. It’s a pretty big table, Table 22. Looks like there’s at least 30 in

there, maybe more.

MS. FIUME: Probably about 48.

DR. LIEBLER: Okay.

DR. BELSITO: I also think that at some point we need to bring in the discussions that we had,

several years back, on the division of these into brown and red and green. And I remember there was information in

those presentations as to some composition that we don’t have here, in terms of general content.

DR. EISENMANN: There’s a table in there that gives it. But, personally, I think you should just

focus on what’s in brown algae and forget the other groups of algae at this point.

DR. BELSITO: No, I understand. But what I’m saying is, is the information that we have here --

the information from that presentation as to what was in brown algae? Because I thought there was more.


DR. EISENMANN: I think it is in there. I’m not sure there's that much more. I think it probably

is what’s in the cell wall, and alginates in the Fucoidan-type materials. I’m not sure there is --

DR. LIEBLER: This is about four years ago --

DR. EISENMANN: Something like that.

DR. LIEBLER: -- that we had this presenter. And I don’t know if Priya’s got those slides in that

deck. If she’s been through the deck, then she’s got it.

MS. CHERIAN: Yeah. It was included in the last pack of information.

DR. LIEBLER: Okay. So we’ve got it.

MS. CHERIAN: Mm-hmm.

DR. LIEBLER: Thank you.

DR. EISENMANN: One thing that struck me, is in the introduction there’s a sentence that more

or less says how different these materials are. I think I would start the introduction differently and say how similar

these -- what the algae have in common, instead of saying how different they are.

And yes, they have some difference; but one thing they do have in common is they’re all marine.

Which does make a difference compared to, like, other groups of algae where you have them growing in all different

types of environments. So, these are all, at least, marine species. Plus they have cell wall materials in common.

I think if you changed the introduction -- to me, when I first read the introduction I thought, if

they’re all so different, why are they being reviewed together. But if you focus on the similarities, in the

introduction, the tone will change and I think it will sound much better than how it’s currently presented.

DR. SADRIEH: And then you also have the reason why it’s appropriate to review them in that

report; bottom line. That's a good idea.

DR. BELSITO: Interestingly, when you look at the sensitization data, we have an HRIPT for

Halidrys Siliquosa, if that’s how you pronounce it, Siliquosa, at 48 percent. It’s not the Laminaria that we asked for,

but it’s a very high percentage. This is on PDF 55, I think. The first paragraph. The extract 48 percent water. I

guess it's the concentration of test substance that's not provided.

I guess that also raises the question, is 40 percent the actual amount of Laminaria, or is it 40

percent of an extract, which contains only a percentage of Laminaria Digitata.

DR. EISENMANN: I’m still trying to get that clarified for sure. But I can only ask, I can’t make


them tell me what’s going on.

DR. LIEBLER: So in other words, the stuff that they used was 48 percent extract in 52 percent

water. The concentration of that stuff, in the material that was applied, is unknown.

DR. EISENMANN: Um hmm.

DR. LIEBLER: Yeah, I think the concept of reading across is really not applicable, with these

complex mixtures, unless we have much more extensive chemical substance characterization. So that we could say

that, for example, with this extract, constituents of concern were similar to, let’s say, fucosa. And then we could

say, well, at least in terms of the concentrations of substance of concern, these are equivalent. But we’re not in any

position to do any sort of read across with these. So, we take the ones we can get and then we decide what that’s

telling us about the overall body.

I’m relatively impressed at the volume of data we’ve got already for these. Considering that half

of the group isn’t even used.

DR. BERGFELD: I’d like to ask a question about that. Couldn’t you divide them into the

GRAS and then enumerate with those? And then the non-use group and then the ones in use, what the testing --

DR. LIEBLER: Oh, that was Ron Shank’s suggestion, originally, how to handle these. The

problem is the ones that are listed as GRAS, are actually, numerically, a small percentage of this whole report. So,

they turn out to be among the ones that are most widely and heavily used. But they don’t help us with very many

ingredients in this report. So then we have to turn to what we had tox data for, also things that are heavily used, but

not GRAS, and where those have a uniformly favorable tox profile based on the data we have.

So, the thing that’s left outstanding, is that for many of the individual ingredients in this report, we

have no data. And so the question is, do we say sort of the biological similarity of these marine organisms allows us

to have confidence in this assessment, overall, based on a lack of any data in the testing materials, showing

significant adverse effects.

And like I said, I started out by saying I’m leaning towards safe as used. I’m waiting to see if

more stuff comes in. I don’t know if we still have requests out for additional data, that haven’t been addressed. Do

you think that this is as good a package as we’re going to have or can we expect more?

DR. SADRIEH: Our feeling is this is probably as good as you’re going to get.

DR. EISENMANN: I’m not aware of anymore coming in, other than maybe a few clarifications


I’m hoping for. But not that I’m aware of. And I think part of the issue of these ingredients, a lot of them are being

sold as even more complex mixtures. So, they’re coming in with other plants, with other algae species. And then

they’re testing those more complex mixtures, rather than testing the algae alone. So, it’s kind of pretty complex.

DR. SNYDER: So, to Wilma's point, maybe the way to approach this report is to have a really

large intro section that really clearly indicates what data we’re utilizing. The GRAS/non-GRAS is obviously very

important. The high-use, high-concentration ingredients. And then, parcel it that way to see where we’re at. That’s

what I was trying to do when I reviewed it. And it was very hard. Every time I thought I had something, then it

wouldn’t clear something else.

And then our discussion is going to have to be very robust in why we we’re leaning towards safe

as use. We don’t have any red flags. But then again, we don’t have all the data that may give us indication of these

red flags. But again, instead of saying safe as used, maybe we need to say, safe as long as they’re within the

composition of the ingredients you reviewed in this report.

So, maybe somewhat different how we state it. Because it is really driven by composition

impurities. We have pulled out the impurities, the heavy metals, the pesticides, the phthalates, and all that kind of

stuff; but we don’t know if there’s others because we don’t have the data.

So we’re going to have to be very specific, if we go safe as used, as to what we’re saying.

Because I think we do have some gaps that are just -- I don’t think we’re going to get the data. I don't even think we

know what data for ask for, to be honest.

DR. BELSITO: If you sort of look at the type of data we’re asking for -- so if you go to Table 8,

this is general compositions of brown algae. I guess this maybe what was presented at our talk several years back.

But then you go down to Table 9, and quite clearly, with the exception of fucus vesiculosus, they’re not really

looking at all the constituents.

So, for the ascophyllum it looks like they were just more interested in the metals. Yeah, because

then they say, water not reported. I mean, you know that there’s water. Carbohydrates, not reported. They’re not

really looking at the entire composition.

And the same thing for the Laminaria. They’re not reporting lots of different factors. So I think

the only one in that table, that comes even close to being complete, is the fucus vesiculosus. But I mean, these

overwhelmingly are carbohydrates, fats and fiber, is what we’re looking at.


DR. LIEBLER: It appears that they did not make measurements of, for example, terpenes and

flavonoids.

DR. BELSITO: Right.

DR. LIEBLER: And those would be what we would be concerned about with most botanicals for

sensitization. And so, we just have no data because for whatever reason it appears they didn’t analyze it. But on the

other hand, the data that we have suggest that there’s no sensitization potential with these. So, I keep coming around

in these circles with these compounds.

The only other thing I can think of is to provide maybe a little more framework and logic behind

our -- I hate to use the term reading across, for lack of a better term -- read across to these is. If we considered what

we have data on by possibly genus, do we have representative data on the genus subgroups. And I didn’t try and

look at that because it would be kind of an onerous exercise. Have you tried to look at it that way, Priya?

MS. CHERIAN: I have not.

DR. LIEBLER: Priya, use the mic please.

MS. CHERIAN: I have not.

DR. LIEBLER: Okay. I mean, right now we’re kind of going by looking at the ingredients that

are used and have the most uses. Those are the ones we tend to have more data for. They’re either GRAS, or we

have data on tox and sensitization and so forth.

And so, for the ones that are used, I’m actually quite comfortable with safe as used. It’s having

half the report -- it's things we have no uses for and no data. So, maybe the decision we’re facing is do we say

sufficient for those? Somehow the ones that are in use, for which we have data, and then for the others not?

Or do we try and group by genus, and make the assumption that within the genus we have

representative data we can read across within that genus. And I’m not sure that’s really valid; but I’m just throwing

that out there to see if anybody else thinks that might be a reasonable approach.

DR. KLAASSEN: I think the approach is reasonable, but I don’t think -- there are so many

classes of compounds here, that’s probably not going to help us.

MS. CHERIAN: I haven’t specifically looked through every genus to see if there was data for

each. But I don’t think there would be enough.

DR. BELSITO: If we did it by subclass, maybe. But getting down to genus, no.


DR. LIEBLER: I mean, if we did it by family.

MS. CHERIAN: It's probably close. Yeah, it's probably close.

DR. SNYDER: The bottom line here is what we really need is more composition data,

particularly organic constituents, because that's what many of the -- that's the uncomfortable. I mean, I guess we

could just keep -- I mean, I don’t know if we’re going to get it, or if it’s not available. We have some, but we

certainly don’t have enough to fill all the gaps. Because it’s such a diverse group.

DR. BELSITO: We don’t even have it for any of them. I mean, Table 8 and Table 9 are it. And

it just lists terpenes, it doesn’t give us percentages.

DR. SNYDER: Well, I guess that, combined with the fact that we didn’t get the 28-day dermal,

to know whether any of them are absorbed, I think we are obligated to go insufficient.

MS. FIUME: I was just going to say there is no -- we’ve done it many times where we've had

split decisions. So, if you find that you can support the safety of some of them, we can go with some type of safe or

safe with qualifications. For those that you don’t feel comfortable that the data are there, insufficient data is always

an option as part of the conclusion. We can do a mixed conclusion.

DR. LIEBLER: That would be the most conservative approach. I think that we would actually

end up covering a lot of the ones that are in use. And then we would not have sufficient data -- we would be

insufficient for some that are in use and everything that’s not in use. And the stuff that's not in use, we’re not going

to get the characterization on that. I mean, it’s just not going to happen.

I think I would favor that approach. I think I could justify that to somebody who is skeptical. And

that’s what our standard should be.

DR. BELSITO: So, then Table 23, Priya did what Ron asked for at the last meeting. And she

has the GRAS substances; and then she has brown algae species used in food products. So, I just didn’t understand

the difference between 23 and 24. All of the ones that are GRAS are used in food products, because you’ve got

Cladosiphon Okamuranus as being used in a food product, but not being GRAS.

MS. CHERIAN: Not all of them are listed as GRAS. But when I did research, I saw some that

are used as food products, but aren’t labeled as GRAS.

MR. GREMILLION: There’s no requirement that a company notify FDA when they make a

GRAS determination. Companies could be operating under self-determination that their product is GRAS. That’s


another complication with classifying it that way.

DR. EISENMANN: But those materials are actually food. They’re not used in food, they’re

food. And one note is -- in Table 24 -- Laminaria Angustata. Well, the INCI name for that one is Saccharina

Angustata. So, if you say the food are safe, then Saccharina Angustata Extract should be safe because that’s the

current name. That’s the difficult part of it now, too, a lot of the names are changing.

DR. BELSITO: Which one are you talking -- which Laminaria?

DR. EISENMANN: Angustata.

DR. SNYDER: Fifth one down.

DR. BELSITO: Oh, okay. So, Dan, your suggestion was to take Table 23, and 24, and say that

those are safe as used; and the others are insufficient based upon dermal absorption or composition? Is that what

you’re saying?

DR. LIEBLER: I would start out as you started out, those in Table 23 and 24, safe as used. And

then I would add, into the safe category, those for which we actually do have tox data, even if it’s not dermal; and

those for which we do have sensitization data. But we could use the body of sensitization data, perhaps, if the

dermatologist agree, to conclude that there’s no potential for sensitization amongst these.

DR. BELSITO: But sensitization data doesn’t get rid of the fact that we don’t have absorption,

and we don’t know what’s in it, getting back to Paul’s point.

DR. LIEBLER: So, okay, here's the -- what I'm suggesting is the first cut. The ones that we

would keep in the report, potentially, as safe as used, would include those that are GRAS, those that are used in

food, and those for which -- if they’re not in either of those tables -- for which we do have tox data, which is like a

couple of fucosas.

And then we take that group and we make a conclusion about sensitization, based on the available

data. That still could be insufficient for some of those, but that’s going to be your call, Don. You and Wilma and

Jim, I think.

And then the others, we don’t really have anything. We can’t read across to anything. And we’ll

simply have to say that those are insufficient. That would probably leave us with, maybe, a dozen or so that clear

the bar, maybe 15. And the rest are going to be insufficient.

DR. SNYDER: A 200-page report just became a 250-page report.


DR. LIEBLER: It’s just bytes on your hard drive.

MS. FIUME: Can I ask a question about looking for the absorption? I often get confused with

this and with botanicals. We state that because they’re large complex mixtures, it’s impractical to look for

absorption data. So, when you’re talking about not having the 28-day dermal, to see what absorbs for the systemic

toxicity, is it because of concerns of specific impurities that may absorb? And that’s where the concern is, not

having any absorption data or 28-day dermal tox?

DR. LIEBLER: You can’t do absorption study with these. Because they’re heterogeneous

mixtures of things that will certainly be absorbed, and things that will certainly not be absorbed. And preparation to

preparation, the amounts absorbed is going to vary as well. Absorption data for these is pretty meaningless.

The only way in which it would make sense, is if there was a particular constituent of concern that

we want to know if it’s absorbed from typical ingredients. You know, fucosa, let’s say. If Laminin were in it, is it

absorbed? If Quercetin were in it, is it absorbed? But we’re not talking about that. We don’t even know if

Quercetin is in it.

We don’t even know what questions to ask in order to do the experiment. And I don’t think we’re

going to get the data. So, I think the issue of the ability to treat these in that way, is just not before us. We really

have to go with the data we have or simply say it’s insufficient. And I think we probably would be better off asking

for tox endpoints than analytical endpoints.

DR. BELSITO: So, then when you’re looking at tox endpoints, I don’t think genotox alone

clears that. And all of the genotox is negative. So, then you’re really looking at, I presume, oral repeat dose studies.

And then where do we cut it off? Do we want at least 13 weeks? At what point do we say we have enough oral tox

to make us feel comfortable?

DR. SNYDER: Typical toxicity studies you start off with acute oral. You get your doses, so you

know -- once you identify your toxicity, then you can escalate longer duration of exposure to see if you have

additional issues. And so, it’s not set in stone, it’s a systematic approach. There is a reason to how you do it. And

so, longer duration gives you more confidence that you have no health concerns.

DR. BELSITO: Right. So, at what point do we want that confidence? Do we want four weeks?

Do we want 13 weeks? Do we want --

DR. SNYDER: Yeah, usually a 4-week study, with very low toxicity, gives me tremendous


confidence on a very low-concentration ingredient. I don’t think we need to go beyond that, and in that regard. But

if there’s constituents of concern, then we know that it takes longer, then -- that’s what I look at when I make an

evaluation. It’s a lot more complicated than it may first seen.

DR. BELSITO: But we don’t know the constituents.

DR. SNYDER: That’s the problem. It’s all about composition. You know, particularly organic

constituents, we don’t know.

DR. BELSITO: So, in the absence of that, is there any length of study, short of a two-year study,

that you would be comfortable with? Because the longest study, I think, we have is 13 weeks.

DR. KLAASSEN: I think we could be -- I could be satisfied with a 4-week study, most likely.

DR. BELSITO: We actually have a 32 and 36 in a lifetime, but most of them are 13 weeks.

DR. LIEBLER: I agree with Curt.

DR. BELSITO: If it’s GRAS, if it’s a food, if we have a 13-week oral, those would be safe as

used.

DR. LIEBLER: Thirteen weeks, we only have --

DR. BELSITO: I mean, 4-week oral. If it’s GRAS, if it’s a food, if we have a 4-week oral, then

we'd be comfortable with it, is that what I’m hearing?

DR. SNYDER: That’s my sense. That's why I said, at the beginning, there doesn’t appear to be

any red flags for anything that we have data on. Even though we don’t have data on as many as I would like to see

us have data on. Or we don’t have composition data on as many as I’d like to see us have data on. It’s just difficult.

It’s a very large, complex group. And it’s hard to get your head around it.

DR. BELSITO: I agree.

DR. SNYDER: But there is no real red flag that I have a big concern about.

DR. BELSITO: Curt, do you have your hand on the mic?

DR. KLAASSEN: Yeah. I was going to ask a general question. Plants often contain these

polyphenolic compounds and terpenoids. Are any of those known to be allergens? I assume they probably are not

because so many plants have them.

DR. LIEBLER: You mean sensitizers?

DR. KLAASSEN: Yeah, sensitizer is what I meant. Can we make a generalization that basically


they’re not sensitizers?

DR. LIEBLER: We don’t have the data on whether they contain any of those compounds. I

would expect they must. But it hasn’t been measured and reported in any of the tables we’re given.

DR. KLAASSEN: I think there is one table on the terpenoids, maybe. But I agree, they weren’t

in here. But they most likely do contain them. But just getting back to the general question, what do we know about

the allergenicity. Are these classes of compounds, terpenoids, et cetera. Are they generally not allergens?

DR. BELSITO: Terpenes are, but not terpenoids.

DR. LIEBLER: Terpenoids is another name that encompasses the terpenes.

DR. BELSITO: Okay.

DR. LIEBLER: So yes, it’s true, Curt. That class does include sensitizers. And it’s like with

citrus. No, citrus isn’t a good example. But it’s like with a lot of botanicals, where one particular plant may have

high levels of a sensitizing terpene. And then others in that family of ingredients don’t. And so, that’s when we

have to start looking at sensitization data and formulated to be non-sensitizing, and so forth.

Here we don’t have anything on the reported levels of those, because nobody’s apparently made

the measurement.

DR. BELSITO: But then can we say when formulated to be non-sensitizing?

DR. LIEBLER: We could. I mean, we usually do that when we know there’s a sensitizer there.

We could extend that logic to say, we don’t know that there’s a sensitizer there, but just in case, formulate to be non-

sensitizing.

DR. BELSITO: And we know they are terpenoids.

DR. LIEBLER: I’m comfortable assuming -- well, put it this way; I would bet in a card game

that there are terpenoids, but we don’t have any data confirming that.

MS. FIUME: But to take that one step further, when we do that with botanicals, when formulated

to be non-sensitizing, it’s because of the overall composition of the ingredient; not because of the concern about the

individual botanical, but botanical in formulation with other botanicals.

DR. LIEBLER: Correct. We almost always do that, because there’s some evidence, under some

condition, that this ingredient that we’re looking at could be sensitizing.

DR. SNYDER: Yes.


DR. LIEBLER: Has constituents of concern. And we don’t have that here, at all.

DR. SNYDER: I don’t think we should use that approach for an absence of data.

DR. BERGFELD: Otherwise, you pass everything.

DR. SNYDER: Yeah. It’s just not the way, scientifically, you look at stuff.

DR. BELSITO: So then, even if we accept the GRAS, the food, the 4-week oral, we’re really not

going to meet the sensitization, except for a few of these. But then we only know that the individual component was

not sensitizing. But in the absence of knowing whether the constituents of that are, and whether there are any

constituents of concern, how do we handle that?

DR. LIEBLER: Well, I think there in the case of the food additives and the foods, in the absence

of data, suggests that these are allergen containing; and as long as a composition of the cosmetic ingredient is

similar, or identical, to the food grade, or whatever, then we are okay with it. Right? Because there are no glaring

reports of people having allergies to the consumption of these products.

DR. BELSITO: But there’s a phenomenon called oral tolerance.

DR. SNYDER: Yes. Right.

DR. BELSITO: And it could simply be that these people are orally tolerized, because they’re fed

these foods from childhood.

DR. SNYDER: Yes. That’s a good point.

DR. LIEBLER: So, if we had a larger body of sensitization data, at concentration of use, even if

we didn’t have it for everything, would that move you closer to comfort on evaluating sensitization? In other words,

how much further would we need to go with human-test data? HRIPTs or something that would alleviate your

concern? Or do you just need sensitization at concentration of use for everything?

DR. BELSITO: Personally, I have not been overwhelmingly concerned with these, as sensitizers,

just looking at the composition. I think you’re largely just putting fiber and carbohydrates on the skin, is what I see

when I look at the overwhelming constituents of these materials. And my only concern is heavy metal and arsenic,

when I look at it. But you’re right, we don’t have the data.

DR. LIEBLER: Right. When you analyze something, you analyze it for specific substances, or

groups of substances, depending on what the analytical method is that you use. And it appears they just haven’t

done the kind of analysis that would identify and quantify flavonoids, polyphenolics, terpenoids, et cetera. It


appears that that hasn’t been done.

We don’t have a column for terpenoids that says, below limit of detection. We have nothing. So,

I think when we say we don’t see any constituents of concern, it’s because nobody looked. It doesn’t mean they’re

not there.

We, basically, have two ways to know if there is a problem there. One is do the measurement, and

then two is do the experiment in the person. And it’s one or the other.

DR. KLAASSEN: In this day and age, looking at the constituents in these ground up plants, let’s

say, is not that difficult anymore. It’s not like it was 30 years ago. And why people don’t have this information is

really kind of amazing. These kinds of studies, analytically, can be done relatively easy in this day and age. And

we would know what flavonoids were there, and triterpenoids, and et cetera. And if there might be some

compounds that we know that are bad. So I guess I’m a little disappointed that there isn’t more information on this.

DR. LIEBLER: They don’t want to know. They don’t want to pay.

DR. BERGFELD: Yes. But if you go back to your tables, which you’ve been reflecting on

intermittently here today, Table 29, Table 30 -- wrong Table 30, does cite some of the irritation studies. They call it

human-irritation sensitization. But they’ve only commented on the irritation. So, there are some endpoints using

something -- there must be about 30 of these in here or more -- I haven’t counted them -- where we actually have an

ingredient that’s had clinical human testing.

DR. BELSITO: But it’s most irritations.

DR. BERGFELD: I said mostly irritation. It says irritating and non-sensitizing a few, but.

DR. BELSITO: But irritation is just a 24-hour patch. So, I mean, the sensitization is much more

limited.

DR. BERGFELD: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14. Fourteen and one.

DR. BELSITO: Right. But in terms of the actual ingredients, the number is smaller. But it

doesn’t address any tox endpoints on these. And so, what I’m hearing is there’s also a concern in the absence of

dermal absorption about toxicity.

DR. LIEBLER: If we have oral tox, acute and repeat dose, then I’m not really worried about

dermal tox. If it’s clean by oral and these are all clean by oral. The only limitation is the number of compounds for

which we have data. And then with dermal irritation and sensitization, I leave it to you guys to determine if we got a


sufficient body of data. On PDF, I guess it’s, 99 -- 98-99 is what Wilma was looking at. We have about a dozen.

DR. BELSITO: Well, irritation. But again --

DR. LIEBLER: No, sensitization.

DR. BELSITO: Sensitization. Table 30. But I mean, a lot of them -- you have two on Fucus

Spiralis. A lot of them are on the same ingredient.

DR. BERGFELD: It won’t support the whole body, but it might support that ingredient.

DR. BELSITO: No. So let me just recap what you’re saying. If we take and create a list of

those that are GRAS, those that are food, and those for which we have a four-week oral or longer, and we cross

reference it to those that have been studied for sensitization, we would go safe as used for that group that falls into

those two columns.

DR. LIEBLER: Correct.

DR. BELSITO: And the rest would be insufficient.

DR. LIEBLER: Correct.

DR. BELSITO: For composition.

DR. LIEBLER: I would say they’d be insufficient for the tox data or the sensitization data.

Because I don’t think we can use the composition to infer safety. The only way that we would be able to use the

composition data, perhaps in a limited sense, is if there was a particular constituent of concern and there was

sensitization occurring. Then we could look at that constituent of concern and maybe help use that to drive our

conclusion. But we’re nowhere near having that type of data.

DR. BELSITO: Okay. So, is anyone going to be able to create this list by tomorrow?

MS. CHERIAN: I’ll give it a try, yes.

DR. SNYDER: The good thing is the one that’s most used, the Laminaria Digitata, it’s GRAS.

It’s going to clear one of the major -- the Macrocystis I think too, isn’t it? Macrocystis?

DR. BELSITO: Yes. Macrocystis is GRAS.

DR. SNYDER: Yeah. So, I think the two major ones will be cleared, which is probably pretty

good, all things considered.

DR. LIEBLER: I think we’re inevitably heading towards a split conclusion here.

DR. BELSITO: The only issue will be that the Laminaria Digitata and the Macrocystis Pyrifera


were not tested at the concentrations that we’re told they’re used at, which is 40 and 36.4 percent respectively.

Again, I don’t have an issue with it, I’m just pointing that out, that we don’t have the sensitization data at the

concentration that we’re told they’re used at.

DR. SNYDER: We have an HRIPT at 10 and 20 percent. So I mean, would we expect

something different?

DR. BELSITO: No. I mean, again, I’m fine.

DR. SNYDER: Okay.

DR. LIEBLER: Yep. I am as well, Dan.

DR. BELSITO: Okay.

MS. CHERIAN: The HRIPT that came in as Wave 3, I think that it might have been diluted

down. So it said 10 and 20 percent, and then when it was actually tested, it was diluted down to 20 percent.

DR. LIEBLER: Oh, I didn’t see that. Your heading, you had tested at 8 to 12 and then 20. So,

we need that clarification in there. So it wasn't down 10 fold or 100 fold.

DR. BELSITO: Again, I’m not really concerned with these as sensitizers.

DR. BERGFELD: It has to be based on your clinical experience or what you’re seeing?

Broadview or everything?

DR. BELSITO: Just looking at the bulk of the material, when you look at --

DR. BERGFELD: We don’t have that.

DR. BELSITO: I understand that, Wilma. But when you look at the fact that -- look at the

composition. I mean it’s carbohydrate and it’s fiber. And there is all this other stuff.

DR. BERGFELD: I know. But the other stuff is what we’re talking about.

DR. LIEBLER: It’s organic, which we originally had a problem with.

DR. BELSITO: Right. Let’s just go back. That’s what, Table 8 and 9? Where’s the

composition? It’s Table 8 and 9, right?

MS. FIUME: Yes. Is that right, Priya? Constituents are in Table 8, on PDF Page 74.

DR. BELSITO: Right.

MS. FIUME: And then Table 9.

DR. BELSITO: So you have, in general, the protein fraction of brown algae is low, 1 to 24


percent dry weight compared to the green. Most have a protein content of 15 percent. Sterols found in brown algae,

we’re not really concerned about those. Terpenes, phenolic compounds and meroterpenes make up three major

classes of secondary metabolites. Reference 41 doesn’t tell us how much.

MS. CHERIAN: Specifics, no.

DR. BELSITO: And then in Table 9, the only one we really have fairly good data on is fucus

vesiculosus.

MS. FIUME: And that references Dr. Duke’s.

DR. BELSITO: Right. And, I mean, when you look at it, it’s huge carbohydrates, huge fiber,

metals, some beta carotene. I just think that’s what all of these are going to look like with variations, but we don’t

know. We’re sort of beating a dead horse. So, where are we going?

DR. SNYDER: Right. I mean, yeah. We’re just chasing our tail here. The composition and

impurities we have, we know the constituents of concern, we can deal with those. The problem is we have to make

a broad assumption, for those we don’t have data for, that we would consider the composition and impurity levels to

be similar to those we have. But that’s a greater leap than we normally make.

I’m comfortable with it, because I can’t understand why they would be different. But I’m not an

algae expert, and so -- I think the way that you said, we go with the food, the food additives, the ones we have

composition tox data on, and then we see what it looks like. And we may be ending up with a handful that are even

remotely used. And so, I get we just don’t know, and see what the data looks like.

DR. BELSITO: Okay. Let me go back. We’re going to ask Priya to put a table together that

groups GRAS food or more than 4-week oral. That’s one list. And then anther list where we have sensitization

data. And any material that appears in both of those lists, we’ll go safe as used. And anything not, we’ll go

insufficient for what?

DR. LIEBLER: For the missing piece.

DR. BELSITO: For the missing piece.

DR. LIEBLER: Either the tox or the sensitization.

DR. BELSITO: Or the sensitization.

DR. SNYDER: And that would be consistent with what we asked for first. The first cut, was we

wanted composition and organic impurities. And then we wanted the 28-day dermal absorption and, if not, other tox


data. So, it’s consistent with what we’ve asked for previously.

MS. FIUME: So, for the purpose of the discussion, when you say tox, as the missing piece, do

you want it to read as 28-day dermal, or do you want it to read --

DR. BELSITO: Twenty-eight-day oral or longer.

MS. FIUME: Okay.

DR. BERGFELD: It’s acute tox.

DR. LIEBLER: I think the acute tox in a repeat dose.

DR. SNYDER: Yeah. We were saying 4-week, right? That’s not acute tox, that would be short

term.

DR. LIEBLER: No. No.

DR. SNYDER: Yeah.

DR. LIEBLER: Okay. Short-term tox, but it could be either oral or dermal.

MS. FIUME: That was the piece that I wanted to make sure we had clarification on.

DR. BELSITO: Oral or dermal.

DR. LIEBLER: That makes sense, doesn’t it?

DR. KLAASSEN: Yeah. I agree.

MS. FIUME: It does. Especially, since the discussion we’ll be stating that you used 4-weeks

oral tox to support safety. So, then that would make sense for the insufficient piece.

DR. LIEBLER: I mean, oral will be satisfactory, dermal will be better.

DR. BELSITO: Okay. So, we don’t know what those ingredients are yet. But if it’s GRAS,

food or we have a greater than 28-day oral or dermal tox, and we also have sensitization on that, it’ll be safe. All the

others will be insufficient for whatever that missing piece is.

DR. LIEBLER: So, if we’re going to have a conclusion tomorrow that we vote on, we’re going

to have to actually be able to assign the ingredients to the conclusion as either safe as used or --

DR. BELSITO: Yes.

DR. LIEBLER: And I’m not sure that we’ll be there tomorrow. I don’t know, Priya, you got a

lot on your plate. I don’t know if it’s possible or not. I mean, is this something that we might need to table until the

next meeting?


MS. CHERIAN: I think I could come up with a list.

DR. KLAASSEN: Make that decision tomorrow.

DR. LIEBLER: I tried to give you a place to hide.

MS. CHERIAN: I appreciate that.

MS. FIUME: She’ll make her best effort to have it for you tomorrow.

DR. EISENMANN: I have one comment that I would like to see corrected in the report. In the

impurity section, there’s a study on phthalates in the --

DR. LIEBLER: What page?

DR. BELSITO: PDF?

DR. EISENMANN: It’s the paragraph right before the use, I don’t have the PDF --

MS. FIUME: Forty-seven.

DR. EISENMANN: -- page. It says that phthalates are at a concentration of 60 to 70 percent in

the algae. I looked that up. The paper actually does say that, but it’s out of context. There’s no way that could be

that much phthalate in it.

What they were doing -- it’s an isotope study, and they were trying to determine if the algae is

actually making the phthalates. And so, they concentrated it very much. And I think those are the concentrations in

the concentrate, in which they were determining how much 14C was in it.

So that their conclusion was, yes, algae can make some phthalates. But they never said how much

is actually in the algae. So, I’d like to see that corrected in the report.

DR. LIEBLER: Yeah, that makes sense. I mean, there’s no way that they could contain 60/70

percent phthalate.

DR. BELSITO: They’d be rather plastic, wouldn’t they?

DR. LIEBLER: That’s right.

DR. EISENMANN: Right. Did they use a (inaudible) -- I mean, why isn’t industry using a

(inaudible) to isolate them, rather than making it from oil?

DR. LIEBLER: You ought to start a company.


DR. BELSITO: So, how would you like that changed?


DR. EISENMANN: To really focus on the conclusion of the paper, that they’ve determined that

they make these phthalates. That they don’t give the concentration of the phthalates in the algae. That’s the

concentration of the phthalates in the material they could measure. I mean, they had to really clean up the algae and

get rid of all the fatty acid and all the other things in order to focus on the --

DR. BELSITO: So, just say they can make phthalates and end it there?


DR. LIEBLER: Right. Leave it at that.

DR. KLAASSEN: Leave out the 60 and 70. No quantification. It’s a qualitative statement here.

DR. BELSITO: So get rid of just the concentration. I’m fine with that. Everyone else?

DR. LIEBLER: Yes.

MS. CHERIAN: Are there any other discussion points that need to be addressed, such as heavy

metals?

DR. BELSITO: Yes. Heavy metals and arsenic.

DR. EISENMANN: What about iodine? Do you want to discuss iodine? Because what this is

used as, is a dietary supplement to provide iodine. And I don’t know if you want that in the discussion or not.

DR. BERGFELD: Yes.

DR. BELSITO: So, exactly -- there were some case reports on this of toxicity from dermal

exposure or just is it oral?

DR. SNYDER: Mic.

DR. BELSITO: Case reports of toxicity affecting thyroid, but that was oral, right? It really

wasn’t -- it was just one.

DR. SNYDER: The thyroid hormone, they increased, but they still were within normal range.

DR. BELSITO: Right.

DR. SNYDER: I didn't flag that at all.

DR. BELSITO: These were extracts for potassium iodine.

DR. SNYDER: We don’t have any composition data on that, that's the problem, so I don't know.

I mean, it's hard to --

DR. BELSITO: Right. Like you said, it was within normal limits.


DR. SNYDER: Yeah. So I didn't flag it at all.

DR. BELSITO: I think we’re okay with that. I think the biggest concern is arsenic and heavy

metal.

DR. SNYDER: And pesticides.

DR. BELSITO: Anything else? Shall we take a little break, give our minds a break? It’s 10:16,

regroup in ten minutes. Is that enough? 10:25, 10:30 at the latest.

Group 2 – Day 1

DR. MARKS: Next -- oh. Brown algae. There’s brown algae. We got a lot of supplemental

data.

DR. SLAGA: A lot of it.

DR. MARKS: Where is -- yeah. Here we go. So, team -- Priya, you’re up again, huh? You’re

the brown algae expert now. I guess I’ll wait until Ron Hill gets back in here. So, Ron Hill already knows this, I’ll

start.

At the September 18th meeting, the panel issued an insufficient data announcement for these 82

ingredients. And Priya listed the needs composition organic constituent, 28-day dermal toxicity, if the ingredients

are not GRAS. I didn’t see which ingredients were GRAS-identified, but I may have overlooked that.

Sensitization data and genotox for ingredients that are not GRAS.

I guess we’d better start. Better wait for Ron Hill. I suspect we’re gonna be issuing a tentative

report with insufficient data, but --

DR. SHANK: For sensitization, right?

DR. MARKS: Yep. How important are the GRAS, Ron, at this point? Was there GRAS

identified in this?

DR. SHANK: Yes.

DR. MARKS: It was. Okay. I missed that.

DR. SHANK: Yeah, it’s in here.

DR. MARKS: Okay. Good.

MS. CHERIAN: Table 23.


DR. SHANK: Table 23.

DR. MARKS: Oh, that’s it. Thank you.

DR. SLAGA: We got a lot of data to go on and read.

DR. MARKS: So, you had the same sensitization I did, Ron Shank, the Laminaria Digitata

Powder at 40 percent, and the Macrocystis Pyrifera Extract at 36 percent? I thought those would be the lead

ingredients for sensitization.

DR. SHANK: And how about Japonica? Laminaria Japonica Powder, 5 percent?

DR. MARKS: Yeah. We could --

DR. SHANK: We have no data.

DR. MARKS: Okay. Well -- so, Ron Hill, basically, I summarize where we were at that point

now to the moving on to a tentative report. We got a lot of data. I think Tom has mentioned that two or three

times, that we got a lot of data, so --

DR. SLAGA: If we wait one more time, we’ll have even more.

DR. MARKS: Yeah. Are the composition and -- so, composition and organic, let’s go down

these one at a time on the data needs. Are the composition and organic constituents now, are they okay? We do

have that issue with heavy metals and arsenic, but I assume we’ll take care of that with the boilerplate.

DR. SLAGA: Yeah.

DR. MARKS: So, Ron Shank, what did you think about the composition constituents?

DR. SHANK: As far as I was concerned, it was okay. Most of these have low use concentrations

in leave-on products.

DR. HILL: Yeah, that's the thing.

DR. SHANK: And the weight of evidence on the sensitization studies, for most of them, seems to

say they’re okay. And the same thing, weight of evidence and systemic toxicology supports at these low doses,

they’re safe. So, it was just insufficient for three, which we’ve identified. Want me to say it again?

DR. MARKS: Yeah. Repeat that. Well, the third one.

DR. ANSELL: Which are the non-GRAS.

DR. MARKS: So, the sensitization, I had the Laminaria Digitata Powder at 40 percent and

Macrocystis Pyrifera (kelp) Extract, at 36 percent.


DR. SHANK: Right.

DR. MARKS: And then, the third one you had, Ron?

DR. SHANK: Laminaria Japonica Powder at 5 percent.

DR. MARKS: Okay.

DR. SHANK: So the only need that I had --

DR. SLAGA: Well, there are plenty of genotoxicity dermal irritation.

DR. SHANK: Right.

DR. MARKS: Okay.

DR. SHANK: One minor point. We might check something on Page 47, under impurities. Near

the top of Page 47, under phthalates, it has dibutyl phthalate and ethylhexyl phthalate at 60 to 70 percent of the

plant. I don’t think that could be right.

DR. ANSELL: No.

DR. SHANK: Now, is that -- maybe have a plant extract?

DR. ANSELL: No. We think it’s 60 or 70 percent of the phthalates found in algae are those two.

DR. SHANK: Oh.

DR. HILL: That sounds --

DR. SHANK: Okay, okay. That makes sense.

DR. ANSELL: Which is substantively different than a material which is 90 percent water, also

containing 70 percent of another material.

DR. HILL: I know of no production of phthalates, by natural organisms, as esters like that. I

guess it’s possible, but I might have not encountered it.

DR. ANSELL: Okay. We would just ask that the paper be reviewed more carefully.

DR. MARKS: Okay. So you have that, Priya?

MS. CHERIAN: Um-hmm.

DR. MARKS: Okay. So, tomorrow -- any other comments? Otherwise --

DR. HILL: Just a general comment. Who normally does the bookmarking of the PDF before it

comes to us?

DR. HELDRETH: The bookmarking kind of occurs automated. We take the different pieces of


a report and form the report.

DR. HILL: I’m talking about in the report. Because most of them will be bookmarked where the

sections of the report are bookmarked

DR. HELDRETH: Right.

DR. HILL: I mean, usually, it’s just one for the tables, but --

DR. HELDRETH: When we bring it into Acrobat, it makes the whole portfolio, it automatically

bookmarks the different pieces that were put in.

DR. HILL: The only reason why I ask is because in this particular case there’s just one

bookmark, for the whole report, and there’s no subsections.

DR. HELDRETH: Yeah. I see that.

DR. HILL: And when we have a really long report with big long tables, it -- that’s why I didn’t

know if that was down to the writers or --

DR. ANSELL: No, that’s at, like, Kevin stage, Kevin and Julia (phonetic) stage. So, we’ll make

sure we fix that.

DR. HILL: Okay. Then it might have just been an oversight in this case, given the timeline

which was tight, really tight.

DR. MARKS: Out of interest, Ron Shank, why did you pick the Laminaria Japonica Powder at 5

percent? The ones I chose are high use, high concentration. There must’ve been something stood out that you

wanted that. And I’m fine. I mean, obviously.

DR. SHANK: Okay. I had that there are four ingredients used in leave-on products at

concentrations greater than 1 percent. And that’s why that one fell in. One of them, Laminaria Digitata Extract, at

5 percent, was tested HRIPT, and not a sensitizer.

DR. MARKS: Right. That was the Wave 3 data on that. Yep.

DR. SHANK: Right.

DR. MARKS: Okay. Good.

DR. HILL: And if you don’t have composition, to know how similar it is to the Laminaria

Digitata, for example, then --

DR. HELDRETH: The conclusion will be --


DR. MARKS: Conclusion will be insufficient data for sensitization of the three ingredients that

we mentioned before.

DR. HELDRETH: Okay.

DR. MARKS: So, all the other ingredients will be safe, and insufficient for these 3.

DR. SHANK: Amazing. That huge list of all kinds of funny things, handled very well.

Congratulations.

MS. CHERIAN: Thank you.

DR. SHANK: You had a very difficult task there.

DR. HELDRETH: She came in midstream, too. She didn’t get to build it from scratch.

DR. MARKS: So, basically, safe for 79 ingredients and insufficient data for sensitization, HRIPT

for 3 ingredients. I wouldn’t be surprised that we see the sensitization data for those 3, since there are a lot of uses,

at least for two of them.

DR. SLAGA: Yep. A lot of uses.

DR. MARKS: Okay. So, presumably, we’ll be seconding a tentative report tomorrow. Let me

save this. And then we’ll make a decision about the next group of ingredients. I had figured that that would take

the whole half, until lunch, but we’ve got 20 minutes more. So, team, I would move on.

DR. SLAGA: Sure.

DR. SHANK: Good.

Day 2

DR. BERGFELD: We did have a handout that came. I guess you received this, Don.

DR. MARKS: Wave 6.

DR. BERGFELD: This is Wave 6.

DR. MARKS: This morning.

DR. BERGFELD: This morning.

DR. BELSITO: This is brown algae. And at the September meeting, we issued an


insufficient data announcement for the 82 ingredients. We wanted composition organic constituent data for

each. Twenty-eight-day dermal toxicity for those that were not GRAS, sensitization data at relevant use

concentrations for all the ingredients, and genotoxicity for those listed that were not GRAS. We received

quite a bit of data, but not necessarily all of the data that we asked for.

We gave Priya a homework assignment, and I'm not going to read all of these. But if you

take out what was handed out this morning by her, the conclusion of our team was that it was GRAS, if it was

a food, if we had oral toxicity studies of four weeks or longer, and -- so, if we had any of those three, and we

also had sensitization data, they would be safe as used. For those that don't have some degree of either

GRAS, food, oral toxicity and sensitization, they'd be insufficient for whatever part was missing.

If you look at the list that was provided, we're prepared to say that Undaria pinnatifida

extract and Undaria pinnatifida cell culture extract, Macrocystis pyrifera (kelp) extract, Alaria esculenta

extract, Laminaria digitata extract, and Laminaria saccharina extract are safe as used.

Going down that list on the first page, all of those ingredients would be insufficient for

sensitization data, as would be the first two ingredients on the second page. The last of the ingredients in the

table would be insufficient for some degree of oral toxicity 4 weeks or longer. And then the remaining 45

ingredients, at the bottom of the page, would be insufficient for both some form of oral toxicity and

sensitization data. That was our conclusion.

DR. BERGFELD: Dr. Marks, comment? Second?

DR. MARKS: I'll second, I think. I want to go back. We, actually, were much more liberal

in the approach. I kind of like how specific you were in creating this table. We felt we could get a safe for

79 ingredient and insufficient data for sensitization on 3 ingredients.

Did you say sensitization for Laminaria digitata powder at 40 percent as safe? And the other

one we had was Macrocystis pyrifera (kelp) extract at 36 percent. We didn't feel there was enough

sensitization data for that. Then the Laminaria japonica powder at five percent. You know what's interesting

because these are botanicals; and if we used the precedent we've set in the past, that as long as it's formulated

to nonsensitizing, we probably could wave the sensitization. Team, do you want to respond to the Belsito's


proposal?

DR. HELDRETH: Historically, for the nonsensitizing caveat with botanicals, we used that

merely for a cumulative effect, not one specific ingredient.

DR. MARKS: Yeah. So, this would go out as a tentative report, so we'd have time to

relook at the proposed conclusions, Don, correct?

DR. BELSITO: Yeah.

DR. MARKS: Yeah.

DR. SLAGA: My concern with the table, it would take me a little time to analyze what you

said, to make sure, with concentrating and everything, that I agree with it, and right now I cannot. It's a lot to

try to -- whereas we picked out the high levels for needing sensitization data, and that's understandable to me,

but I would have to study each one of the ones, and how you have it listed, and I just can't do that this quickly

at the meeting. So, we could table or something else.

DR. MARKS: Yeah, Tom, and Ron, and Ron, so why did -- we have GRAS, and food, and

tox columns here; why was it that we felt that the systemic toxicity was not going to be an issue for 79 of the

ingrediants -- for all the ingredient, essentially? We just had sensitization concerns.

DR. HILL: I think the basis was -- and I was going to ask this sort of rhetorical question,

why do we care about oral toxicology information when these are used primarily -- well, maybe exclusively --

dermal roots of exposure at low concentrations of use. We may have substances in there that would be taken

out by -- unless you use huge whopping doses for the oral toxicology study, by first-pass metabolism, and we

wouldn't know about anything that was happening in the skin or in nearby areas. On the other side is, they're

used at low concentrations. So, I'm not sure that oral systemic toxicology tells us anything of any use

informing -- versus the art of use.

DR. SNYDER: We could modify that to say that we want -- instead of oral tox, we can

modify it to our standard 28-day dermal, and if absorbed, then we may want additional tox data.


DR. BELSITO: I think our issue -- and I'll let Dan address this -- is we don't really have

good data on constituents. We have very broad ranges, like it contains terpenoid; but what terpenes does it

contain? We have asked for composition data and we really never got a lot of specific composition data. So,

yeah, there's a lot of fiber, it’s a lot of carbohydrate, but what else is in these? And that we don't really know.

DR. LIEBLER: So, when we use the formulated to be nonsensitizing construct, to my

recollection, we've always had some data indicating that there was a sensitizing chemical of concern in the

ingredient; and we just didn't know how much would be applied and that's why we used this construct. Here,

we don't even have that information for any of them. It's just a glaring omission, in my view. Nothing on

polyphenols or -- it says there are polyphenols, but doesn't say which ones. Nothing on terpenoids. It says

they're there, we don't know which ones.

Some of these are going to be the ones that are going to produce the problems. If we had

representative data, we could probably deal with it. I'm not necessarily objecting to the formulated to be

nonsensitizing here, but I think we've always done that when we had evidence that there is something

sensitizing in there. All we have here are the test data from the limited number of compounds that have

actually been tested. And then other than that, we've got nothing.

DR. BERGFELD: Any other discussion or a second to the motion? Or a new motion?

DR. HILL: So, if we have GRAS, we're still not sure -- is what you're saying -- about

dermal sensitization?

DR. LIEBLER: Right. So, the GRAS and food additives, actually, as I recall, it was Ron

Shank's suggestion how to take a first cut out of these ingredients. Those that were GRAS for some sort of

use, or also consumed in foods, could be safely presumed to not have a systemic toxicity risk; and then it

would be more of an issue of skin sensitization or irritation. I thought that was reasonable, but I didn't have a

good feel for how many of those actually fell into that category. Then we had some that were the tox data

and that's why I asked Priya if she could make this little table for us, which helps clarify my thinking on this.

So, I'm not sure how we bring in the others with the lack of sensitization data, and without

making some assumptions and going a little bit beyond our approach to formulated to be nonsensitizing. I


don't necessarily object to it, but I wanted to point out that this is different from the situation that we've

applied this to in the past.

DR. MARKS: Yeah, I think my response to that was because we had three ingredients, we

identified we wanted to see sensitization data. With you having a long list of ingredients, it's quite a bit.

Team, should we -- this is going to go out as a tentative report. I don't want to delay that.

DR. BERGFELD: It's not been seconded. That's the motion on the table.

DR. MARKS: I know. So, should we second and then go and deal with the information

from the table? I'd like Ron Shank to comment, because Ron surprised me when he suggested that all would

be safe other than the three ingredients for sensitization. I'd be interested in how you got past GRAS and the

ones that are not GRAS.

DR. SHANK: I looked at the use concentration in leave-on products, and for most of them

the concentrations are very, very low, where I would not expect systemic toxicity from this class of

compounds. It's a weight of evidence based on the whole lot at such low concentrations. The sensitization,

we agree with you on some of them. But if you're going to ask for sensitization on every one, now we go

back to Dr. Belsito's concern, what kind of sensitization data do you want? LLNA's enough? Or you could

do an HRIPT on every one and then you say, well, that's not very good because you don't know where it's

applied.

DR. BELSITO: I mean, the LLNA would give us the best data if you can clear it with

LLNA concentrations that are very high. I would agree with you, just looking at these, I doubt that they

would be sensitizers. But we don't have information on composition. And as Dan pointed out, the ones that

we're worried about are just listed as being present. They’re are terpenes. What terpenes? What percentage?

We don't have that information.

One of the other things we kicked around was trying to look at compositions of families to

see how similar, across the board, rather than asking for compositions for all of these, take one representative

family and look at it. But we don't have that data. It's just that we're dealing here with a lot of absence of

data. A lot of these aren't used. I think we're clearing -- at least, my suggestion would clear those that are in


major use. It's just that we're making decisions, again, without any information.

And I would agree with Bart's point, and Dan's point, formulated to be nonsensitizing is

when we have a signal. If a botanical contains limonene, and we don't want to add it with another botanical,

that contains limonene, that could get it to a sensitizing concentration; or we have a positive LLNA, or we

have a positive guinea pig maximization test.

The sensitization data that we have is clean. So, what is the rationale for asking, or saying,

to be formulated when nonsensitizing when we don't have that data? I had issues with that. And it may be

that we never get this data.

But I think we've cleared the majority of those that are used by saying, okay, if we have oral

tox, or some degree of safety in terms of internal side effects, 28-day dermal, however you want to do it, and

it clears sensitization, than that's fine. Perhaps the easiest way for industry to do this would be to get us some

further data on composition of the families, so we could compare across and then we could probably say all

of them are safe as used.

DR. BERGFELD: So, we have a motion that Dr. Belsito's put on. You want to restate that

motion, and we can see if we can move forward?

DR. BELSITO: The motion was to look at those ingredients that were GRAS, food, or we

had a four-week or longer oral study that was negative, meeting any of those three criteria. And then some

degree of sensitization data. I would agree with Jim, for laminaria digitata, we don't have it up to 40 percent;

for Macrocystis, we don't have it up to 36.4 percent. But as Carol pointed out, it's really not clear that those

are the actual concentrations being used.

From reading the data, I would suspect that that is, in fact, correct; because these are not

provided as a hundred percent pure substances and they're diluted down. We do have the Laminaria, maybe

at 20 percent, maybe not at 20 percent. We're not even sure on that, which comes close to 40.

I think that we have at least some data to go on to suggest they're not sensitizing. So, there

were one, two, three, four, five, six. The top six were fine, safe as used. The whole rest of the first page, and


the first two on the second page, needed sensitization data. The remaining in the table required some degree

of lack of systemic toxicity out of the 28-day dermal, oral, they're not GRAS or food. And the other 45, we

absolutely had no data on.

DR. BERGFELD: That's a motion to move forward with?

DR. BELSITO: That was a motion.

DR. MARKS: Second.

DR. BERGFELD: Second. Any further discussion then? I'm going to call the question.

All those in favor of safe with these limited numbers of ingredients within this document? Okay.

Unanimous.

Now, on the ones that we do not have data on, do we need to make a list of things that we

need? Obviously, composition, sensation, and acute toxicity or 28-day?

DR. BELSITO: Well, I mean, from the list Priya put together, we have those that require

sensitization. We have those that require some degree of systemic toxicity or lack thereof, and those that

require both. Or the alternative is to have industry look at the different families and get us some better

composition data; and then that way, we might be able to read across all of them and say they're all fine.

DR. BERGFELD: So, there are two opportunities offered here?


DR. BERGFELD: Okay. And, Monice, are you okay with this?

MS. FIUME: Yes.

DR. LIEBLER: Well, one minor point for Priya. Priya, thank you for putting figure one in

the flowchart on the ingredient preparation. I think it needs one more iteration. What I was hoping, is that at

the bottoms of the branches would end in like, extract, powder. You know, so you can see where these are

going, because it's not clear what this means right now. I think that might be helpful, and I'm sure you can do


that. Thank you.

DR. BERGFELD: Alex, any comment? Carol? You understand what's needed then? All

right. Then we'll move on. Oh, Ron Hill, excuse me.

DR. HILL: Ten-second clarification. So, when you say systemic toxicity, did we want to

specify that our preference would be 28-day dermal? Or are we leaving it open-ended for now?

DR. BELSITO: I think 28-day dermal, 4-week oral; I mean, there are many ways of

satisfying this, leave it open. Or provide us with composition that we can read across to others.

DR. BERGFELD: Okay. All right. Let's move on the next ingredient in this reports

advancing group, the Basic Red 76. Dr. Marks.


Safety Assessment of Brown Algae-Derived Ingredients

as Used in Cosmetics

Status: Draft Final Report for Panel Review Release Date: March 15, 2019 Panel Meeting Date: April 8-9, 2019

The 2019 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Ronald A. Hill, Ph.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; James G. Marks, Jr., M.D.; Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Executive Director is Bart Heldreth, Ph.D. This report was prepared by Lillian C. Becker, former Scientific Analyst/Writer and Priya Cherian, Scientific Analyst/Writer.

© Cosmetic Ingredient Review 1620 L Street, NW, Suite 1200 ♢ Washington, DC 20036-4702 ♢ ph 202.331.0651 ♢ fax 202.331.0088

[email protected]



ABSTRACT The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) assessed the safety of brown algae-derived ingredients;

82 brown algae-derived ingredients were found in the in the web-based International Cosmetic Ingredient Dictionary and Handbook (wINCI; Dictionary), however, several of these ingredients may be equivalent according to accepted scientific names. The Panel reviewed the available data to determine the safety of these ingredients, which are frequently reported to function in cosmetics as skin-conditioning agents. Impurities, particularly arsenic, may be present in these ingredients. Industry should continue to use good manufacturing practices to limit these possible impurities. The Panel concluded that 6 brown algae-derived ingredients are safe in cosmetics in the present practices of use and concentration described in this safety assessment. The Panel also concluded that the data are insufficient to determine the safety of the remaining ingredients under the intended conditions of use in cosmetic formulations. [Please note, these numbers may change based on additional information that was submitted after the Tentative Report was issued.]

INTRODUCTION

This is a safety assessment of brown algae-derived ingredients as used in cosmetics. The ingredients in this review are extracts, powders, juices, or waters derived from one or multiple species of brown algae. A total of 82 International Nomenclature Cosmetic Ingredient (INCI) names identifying brown algae-derived ingredients (Table 1) were found in the Dictionary; however, several of these ingredients appear to be equivalent based on the accepted scientific name, as given in the definition (Table 2).1 Accordingly, the total number of distinct cosmetic ingredients is 74.

These ingredients are a highly complex group, all of which are marine-derived, with intricate chemistry and compositions. According to the Dictionary, these brown algae-derived ingredients are most commonly used as skin conditioning agents (Table 2).1 These ingredients are also reported to be used as absorbents, antioxidants, binders, hair conditioning agents, oxidizing agents, pH adjusters, and viscosity increasing agents. The safety of these ingredients was assessed based on the availability of systemic toxicity data, via oral repeated dose toxicity studies, use in food, generally recognized as safe (GRAS) status, and on local effects such as sensitization.

There are several major groups of algae (as described in “Algae Identification” section). However, this safety assessment focuses only on brown algae. The names of the ingredients in this report are written in accordance with the INCI naming conventions, i.e., capitalized without italics or abbreviations. When referring to the algae from which these ingredients are derived, the standard taxonomic practice of using italics is followed (e.g., Agarum cribrosum). The term “kelp” is commonly used when referring to brown algae. Kelp are large brown algae that belong to the order Laminariales.2

Several brown algae constituents, such as phytosterols,3 phytosteryl ingredients,3 and alginic acid4 were found to be safe as used by the Panel. The full reports on these ingredients can be accessed on the CIR website (https://www.cir-safety.org/ingredients); therefore, information regarding these ingredients will not be included in this report.

This safety assessment includes relevant published and unpublished data that are available for each endpoint that is evaluated. Published data are identified by conducting an exhaustive search of the world’s literature. A listing of the search engines and websites that are used and the sources that are typically explored, as well as the endpoints that CIR typically evaluates, is provided on the CIR website (https://www.cir-safety.org/ supplementaldoc/preliminary-search-engines-and-websites; https://www.cir-safety.org/supplementaldoc/cir-report-format-outline). Unpublished data are provided by the cosmetics industry, as well as by other interested parties.

The European Chemical Agency (ECHA)5,6 website provides summaries of data generated by industry, and is cited throughout the report as appropriate. Also referenced in this safety assessment are summary data found in other reports, including those published by the European Medicines Agency (EMA),7,8 the European Food Safety Authority (EFSA) Panel on Dietetic Products, Nutrition and Allergies (NDA),9 and Food Standards Australia New Zealand (FSANZ).10,11

CHEMISTRY

Definitions

The ingredients in this safety assessment are derived from various species of brown algae. “Algae” is not a taxonomic group, but a functional group of convenience.12 Not all algae should be considered to be plant-like (seaweed; macroalgae). While some algae are seaweed, some are protozoa, and some are unique and belong in other kingdoms. However, these aquatic and oxygenic organisms are all part of the eclectic group called “algae.”

Algae Identification

There are several major groups of algae, and they are commonly referred to as brown algae (Phaeophyceae), green algae (Chlorophyta), diatoms (Bacillariophyceae), chrysophytes (Chrysophyta), blue-green algae (Cyanophyta), red algae (Rhodophyta), dinoflagellates (Pyrrhophyta), and euglenoids (Euglenophyta). A description of these major algal groups can be seen in Table 3. The different types of algae are differentiated by storage products, pigmentation, and cell wall composition.12 A list of the brown algae-derived ingredients, based on their subclass, order, family and genus, is presented in Table 4.


https://www.cir-safety.org/ingredients

https://www.cir-safety.org/ingredients

https://www.cir-safety.org/supplementaldoc/preliminary-search-engines-and-websites

https://www.cir-safety.org/supplementaldoc/preliminary-search-engines-and-websites

https://www.cir-safety.org/supplementaldoc/cir-report-format-outline

Brown algae are mostly comprised of large, leathery seaweeds and are classified in about 265 genera with more than 1500 species.12,13 The actual color varies depending on the proportion of brown pigment (fucoxanthin) to green pigment (chlorophyll). This algal group contains alginic acid and fucoidan in its complex cell walls. General characteristics and the geographic distribution of the specific species of brown algae included in this report are presented in Table 5.

As with plant-derived ingredients, the constituent composition of these seaweed ingredients can vary widely depending on growing conditions, age of the organisms, local environmental aspects, harvesting conditions, methods of extraction, and many other variables. For example, the concentration of the most abundant carotenoid pigment in brown algae, fucoxanthin, varies remarkably depending on the age of the alga, and the protein content in brown algae varies considerably depending on the season in which it is harvested.14,15

Physical and Chemical Properties

Physical and chemical properties of Ascophyllum Nodosum Extract, Ascophyllum Nodosum Powder, Ecklonia Cava Extract, and Halidrys Siliquosa Extract (aq.) are presented in Table 6. Using the sieve method, 93.5% of the particle sizes of Ascophyllum Nodosum Extract, as a fully dried extract, were less than 0.250 mm and greater than 0.045 mm.6

Harvesting

Originally, the only source of brown algae was in the wild; but since the mid-twentieth century, demand has exceeded the supply that could be harvested from wild sources, and methods for cultivation have been developed.16 Consequently, today, commercial brown seaweed comes mainly from farming rather than wild sources. Laminaria japonica and Undaria pinnatifida are among the most cultivated species of brown algae.17 Several species, such as Laminaria japonica, are grown on suspended ropes in the ocean.16 Repeated harvesting of Macrocystis pyrifera over a 3-month period did not significantly impact tissue chemical properties (i.e. alginate yield; viscosity and strength; nutritional quality, such as protein, carbohydrate, lipid, crude fiber, ash, and energy content; and tissue carbon/nitrogen ratios).18

Method of Manufacture

Numerous methods of manufacture are provided in Table 7. Several of these methods have a target constituent or composition (e.g., high in fucoidan). The characterization of the final extract is provided in the table. A general overview of a method of manufacture for the relevant brown algae-derived ingredients can be seen in Figure 1.


Figure 1. Overview of methods of manufacture for brown algae-derived ingredients. 1,9,19-28,28-52, CIR STAFF

Arsenic is a constituent of concern in certain brown algae [see Constituents of Concern].10,11,53,54 There are methods to remove the arsenic, including extraction with water, methanol, or water/methanol mixtures accompanied with sonication or mechanical agitation.55 Extraction with microwave-assisted heating and accelerated solvent extraction systems are described in the literature.55 Soaking the algae in water at room temperature followed by simmering in the water is shown to be effective for removing inorganic arsenic.56 Another variation entails repeated boiling in seawater, and replacing the water three times, after initial soaking.53 Soaking the algae in a simmering 4% acetic acid or a 4% sodium hydrogen carbonate aqueous solution has also been shown to remove arsenic.57

Composition

Some constituents and constituent groups that are found in brown algae, in general, are presented in Table 8; included therein are alkaloids, laminarins, pheromones, phytohormones, terpenoids, amino acids, betaines, and characteristic pigments such as chlorophyll a and c, β-carotene, fucoxanthin, and several other xanthophylls.58 Constituents found in Ascophyllum nodosum, Fucus vesiculosus, and Laminaria digitata are listed in Table 9.

According to a study, Sargassacean brown algae species biosynthesize mainly meroditerpenes and linear diterpenes, whereas most compounds from the Dictyotacean species are cyclic diterpenoids, sesquiterpenes, and various types of meroterpenes.59 Algae of the family Sargassaceae are among the most prolific in terms of terpene yield. In the genera Cystoseira, Sargassum, and Halidrys, meroditerpenoids constitute the most common metabolites. In the genus Cystoseira, meroditerpinoids could be classified into specific groups dependent upon the structure of their diterpene side chain: linear, monocyclic, bicyclic, or rearranged. The organic extracts of Cystoseira amentacea var. stricta contain high amounts of methoxybifurcarenone.

Sterols are also found in brown algae.60,61 Sterols reported to be in Cystoseira tamariscifolia, Fucus spiralis, and Sargassum vulgare are provided in Table 10.

Harvesting

Extraction with solvent (extract-type ingredients may be obtained via the

steps below)

butylene glycol; H20; caprylic/capric

triglycerides; propylene glycol; CO2

addition of preservatives

filtration

quality control

packaging

ethanolic solution

concentrated and freeze-dried

diethyl ether

vaccuum distillation

supercritical CO2 extraction

liquid-liquid extraction

Extracting with water (water-type ingredients

may be obtained via these steps)

fucoidan purification

ultrafiltration

Washing/Grinding (powder (or juice, if a liquid is expressed)) ingredients may be

obtained at this point


Methanol, hexane, and chloroform extracts from Cystoseira compressa were examined for flavonoid and phenolic content.62 The flavonoid content of the methanol, hexane, and chloroform extract, were 0.291 ± 0.02, 0.88 ± 0.07, and 0.804 ± 0.07 mg/g, respectively. The phenolic content of hexane (1.541 ± 0.09 mg/g) was considerably higher than the phenolic content of the methanol (0.161 ± 0.08 mg/g) and chloroform (0.45 ± 0.04 mg/g) extracts.

Constituents of ethanolic extracts of Fucus spiralis and Sargassum vulgare are presented in Table 11. The constituent with the highest concentration in both extracts is vaccenic acid (21,690 and 2848 ppm, respectively).63

Approximately 0.64 – 1.99 grams of polyphenols can be found in Himanthalia elongata extract.64 In addition, phlorotannins can also be found in this extract (0.2 % dry weight). These include fucols, diphloroethol, and several fucophloroethols. Polyphenols are also found in Undaria pinnatifida extract in amounts of 0.08 – 0.60 g/ 100 g extract. Fucoidans extracted from the sporophylls of Undaria pinnatifida show a higher sulfate and l-fucose content than other fucoidans. The concentration of polyphenols in an aqueous extract of Halidrys siliquosa was reported to be 0.16 %.65 The total protein and mineral content present in Halidrys siliquosa is approximately 9.6 and 11.19%, respectively.

The composition of a water/propylene glycol extract of Laminaria japonica is provided in Table 12.51 The compositions of extracts of Laminaria japonica52 that are produced via enzyme hydrolysis are presented in Table 13.

The specifications for an alcohol extract of Ecklonia cava, as a food/dietary supplement, include a combined phlorotannin content of 90.0 ± 5.0%; the content of dieckol, a specific phlorotannin, is 6.6% to 9.9% (Table 14).9 The extract is to contain no insoluble substances, and it is reported to contain calcium (4800 ± 400 mg/kg), magnesium (1300 mg/kg), potassium (700 ± 200 mg/kg), and iodine (220 ± 40 mg/kg).

An Undaria pinnatifida extract rich in fucoidan was characterized as having 27% uronic acid, 53% monosaccharides, and 7.4% sulfate.66 Major monosaccharides included 54% fucose and 35% galactose. The minor monosaccharides were 3% rhamnose, 4% arabinose, and 1% xylose, glucose, and mannose.

A desalinated Undaria pinnatifida powder was reported to consist of 532 mg/g dietary fiber, mostly in the form of alginates, and 209 mg/g protein.67 The composition profile is presented in Table 15.

A study was performed to determine the flavonoid content of several species of algae.68 Results of this study are presented in Table 16.

Impurities/Constituents of Concern

Possible allergens listed in Annex III of EU Cosmetic Regulation (EC) No. 1223/2009 found in trade name mixtures containing relevant brown algae-derived ingredients can be found in Table 17.

Arsenic Arsenic, usually in the form of arsenosugars, is a natural constituent of some brown algae, including Ecklonia

radiate, Laminaria japonica, and Sargassum fusiforme.10,11,52,54,69 The amount of arsenic is inconsistent due to varied uptake of inorganic arsenic by brown algae varieties and the influence of external factors (e.g., temperature, season, and pH). A trade name mixture containing 4.7% Ascophyllum Nodosum Extract in 94.5% water was reported to have ≤ 2 ppm arsenic.70 The amounts of arsenic that have been measured in various brown algae are presented in Table 18. The different arsenic-containing moieties found in four brown algae species are presented in Table 19. A comparison of the amount of arsenic found in Laminaria japonica and a Laminaria japonica extract (equivalence to cosmetic ingredients not confirmed) is presented in Table 20. Heavy Metals

Brown algae, in general, exhibit an affinity for heavy metals, which are believed to be absorbed from the water column.58,71 Heavy metal concentrations in algae are strongly dependent on environmental parameters of the sampling sites (e.g., salinity, temperature, pH, light, nutrient concentrations, oxygen, etc.) and the structural differences among the algae. These seaweeds also absorb heavy metals from the sediment.72,73 A trade name mixture containing 4.7% Ascophyllum Nodosum Extract in 94.5% water was reported to have ≤ 20 ppm heavy metals.70 An overview of the amount of heavy metals found in brown algae species is provided in Table 21. Information regarding heavy metal impurities in trade name mixtures containing brown algae can be found in Table 22.

An edible, phlorotannin-rich, ethanol extract of Ecklonia cava has specifications issued by the European Commission.9 According to the Commission, this extract must contain < 3 mg/kg lead, < 0.1 mg/kg mercury, < 3 mg/kg cadmium, < 25 mg/kg arsenic, and 150 - 650 mg/kg iodine.

Phthalates

Dibutyl phthalate (DBP) and di-(2-ethylhexyl) phthalate (DEHP) were shown to occur naturally in Laminaria japonica.74 These phthalates were also present in Undaria pinnatifida.


USE Cosmetic

The safety of the cosmetic ingredients included in this assessment is evaluated based on data received from the US Food and Drug Administration (FDA) and the cosmetic industry on the expected use of these ingredients in cosmetics. Use frequencies of individual ingredients in cosmetics are collected from manufacturers and reported by cosmetic product category in the FDA Voluntary Cosmetic Registration Program (VCRP) database. Use concentration data are submitted by the cosmetic industry in response to surveys conducted by the Personal Care Products Council (Council), of maximum reported use concentration by product category.

According to VCRP data received in 2019, Laminaria Digitata Extract is reported to be used in 310 formulations (229 in leave-on formulations, 74 in rinse-off formulations, and 7 diluted for the bath; Table 23).75 Fucus Vesiculosus Extract is reported to be used in 291 formulations, Macrocystis Pyrifera (Kelp) Extract in 199 formulations, and Ascophyllum Nodosum Extract is used in 140 formulations. All other in-use ingredients are reported to be used in 136 formulations or fewer.

Ascophyllum Nodosum Extract was reported in the VCRP as Ascophyllum Nodosum (Seaweed) Extract and Fucus Vesiculosus Extract was reported as Fucus Vesiculosus (Bladderwrack) Extract. Laminaria Saccharina Extract is reported in the VCRP as Saccharina Latissima (Kelp) Extract; the accepted scientific name for Laminaria saccharina is Saccharina latissima.

The results of the concentration of use surveys conducted by the Council in 2015 and 2016 indicate Laminaria Digitata Powder has the highest reported maximum concentration of use; it is used at up to 40% in face and neck formulations.76,77 Macrocystis Pyrifera (Kelp) Extract is reported to be used at up to 36.4% in eye lotions. The other ingredients are reported to be used at 6% or less.

In some cases, reports of uses were received in the VCRP, but concentration of use data were not provided. For example, Ascophyllum Nodosum Powder is reported to be used in 4 cosmetic formulations, but no use concentration data were reported. In other cases, no uses were reported in the VCRP, but concentration of use data were reported in the industry survey; Fucus Vesiculosus had no reported uses in the VCRP, but a use concentration in shampoos, moisturizing formulations, and suntan formulations was provided in the industry survey. Therefore, it should be presumed there is at least one use in every category for which a concentration is reported. The ingredients not in use according to 2019 VCRP data and the 2015 and 2016 Council surveys are listed in Table 24.

Several of these ingredients are used in formulations that are used near the eye (e.g., Macrocystis Pyrifera (Kelp) Extract at up to 36.4% in eye lotion and Fucus Vesiculosus Extract in mascara at up to 5%), incidentally ingested (e.g., Macrocystis Pyrifera (Kelp) Extract in lipsticks at up to 0.079%), and in formulations that come in contact with mucous membranes (e.g., Fucus Vesiculosus Extract and Laminaria Digitata Extract at up to 5% in bubble baths and Laminaria Japonica Extract and Macrocystis Pyrifera (Kelp) Extract at up to 5% in bath oils, tablets and salts).

Additionally, some of the brown algae-derived ingredients are used in cosmetic sprays and could possibly be inhaled; for example, Macrocystis Pyrifera (Kelp) Extract is reported to be used at up to 0.79% in spray face and neck products. In practice, 95% to 99% of the droplets/particles released from cosmetic sprays have aerodynamic equivalent diameters > 10 µm, with propellant sprays yielding a greater fraction of droplets/particles < 10 µm compared with pump sprays.78,79 Therefore, most droplets/particles incidentally inhaled from cosmetic sprays would be deposited in the nasopharyngeal and thoracic regions of the respiratory tract and would not be respirable (i.e., they would not enter the lungs) to any appreciable amount.80,81 Laminaria Japonica Extract and Macrocystis Pyrifera (Kelp) Extract were reported to be used in face powders at concentrations up to 0.0035%. Conservative estimates of inhalation exposures to respirable particles during the use of loose-powder cosmetic products are 400- to 1000-fold less than protective regulatory and guidance limits for inert airborne respirable particles in the workplace.82-84

None of the brown algae-derived ingredients named in this report are restricted from use in any way under the rules governing cosmetic products in the European Union.85

Non-Cosmetic

Brown seaweeds are consumed around the world and come mostly, but not only, from the Laminaria, Undaria, and Hizikia genus.16 According to the US FDA, brown algae (i.e., several species of seaweeds that are harvested principally in coastal waters of the northern Atlantic and Pacific oceans) are direct food substances that are GRAS for human consumption for use as flavor enhancers and flavor adjuvants, when the maximum level in food does not exceed the current good manufacturing practice (cGMP). [21CFR184.1120] “Kelp” (the dehydrated, ground product prepared from Macrocystis pyrifera, Laminaria digitata, Laminaria saccharina, and Laminaria cloustoni) is approved as a food additive for direct addition to food for human consumption as a source of iodine or as a dietary supplement. [21CFR172.365] An overview of the species of brown algae that are GRAS in the US can be seen in Table 25. In New Zealand, Japan and other Asian countries, dried sea kelp is a common food; the exact species of kelp used varies according to location.16 The EFSA NDA Panel concluded that an alcohol extract of Ecklonia cava is safe for the use in food supplements at a maximum intake level of 163 mg/day for adolescents from 12 to 14 years of age, 230 mg/day for adolescents above 14 years of age, and 263 mg/day for adults.9 In addition, a listing of brown algae species that are frequently ingested by humans is provided in Table 26.


Several genuses of edible brown algae include Alaria, Himanthalia, Laminaria, Saccharina, Undaria, Ascophyllum, Fucus, Sargassum, Hizikia, Dictyotales, and Eisenia. 86

In France, some varieties of seaweed have been authorized for use as vegetables and condiments.87 These include Ascophyllum nodosum, Fucus vesiculosus, Fucus serratus, Himanthalia elongata, Undaria pinnatifida, Laminaria digitata, Laminaria saccharina, Laminaria japonica, and Alaria esculenta. These algae, when used in this manner, must not exceed certain levels of toxic minerals (≤ 3 mg/kg arsenic, ≤ 0.5 mg/kg cadmium, ≤ 0.1 mg/kg mercury, ≤ 5 mg/kg lead, ≤ 5 mg/kg tin, and ≤ 2000 mg/kg iodine.

In animal drugs, feeds, and related products, brown algae (kelp; Laminaria spp. and Nereocystis spp.) are GRAS as natural substances [21CFR582.30] and as solvent-free natural extractives [21CFR582.40] used in conjunction with spices and other natural seasonings and flavorings.

In the US, “kelp” is present in OTC dietary supplements for weight loss. [21CFR310.545] However, there are inadequate data to establish a general recognition of the safety and effectiveness of this ingredient for that specified use. Several other sources refer to the use of Fucus vesiculosus for weight loss.88,89

Pastes of seaweed, made by cold grinding or freeze crushing, are used in thalassotherapy, in which the pastes are applied to the body and then warmed under infrared radiation.16 This treatment, in conjunction with seawater hydrotherapy, is said to provide relief for rheumatism and osteoporosis. In folk medicine, preparations of Fucus vesiculosus are used to treat hypothyroidism, iodine deficiency, arteriosclerosis, digestive disorders, menstrual abnormalities, cellulite, and sprains.88,90 In herbal folk medicine, Laminaria hyperborea is used for thyroid regulation, and Macrocystis Pyrifera is used to treat thyroid conditions, anemia in pregnancy, and hypertension, for bringing about weight loss, and as an immunity booster.88

Brown algae have been used as fertilizers and soil conditioners (Ascophyllum, Sargassum, Ecklonia, and Fucus species), animal feed for sheep, cattle, horses, pigs, and chickens (Alaria esculenta, and Ascophyllum and Laminaria species), feed and feed binder for fish and abalone (Macrocystis pyrifera), and biomass fuel (Macrocystis pyrifera), and they have been used for waste water/effluent treatment and removal of heavy metals (Sargassum, Laminaria, and Ecklonia species).16,58 Brown algae are used as biomonitors for heavy metal pollution in estuarine and coastal waters worldwide, and to evaluate the quality of their surrounding environment.71

TOXICOKINETIC STUDIES

Obtaining data on the toxicokinetics of uncharacterized, complex mixtures would be impractical, as is the case with many botanical ingredients. No toxicokinetics studies were discovered in the published literature, and no unpublished data were submitted.

TOXICOLOGICAL STUDIES

Acute Toxicity Studies No acute dermal or inhalation toxicity studies were discovered in the published literature, and no unpublished data

were submitted. Acute oral toxicity studies summarized below are presented in Table 27. Oral

The LD50 was > 2000 mg/kg when Sprague-Dawley rats were dosed with Ascophyllum Nodosum Extract. No other details regarding this study were provided.91 Cystoseira Compressa Extract was not toxic to mice when given a single dose of up to 2000 mg/kg by gavage.62 No animals died when Sprague Dawley rats (10/sex) were given 2000 mg/kg Ecklonia Cava Extract (alcohol extract) by gavage.9 Similarly, no abnormalities were seen when Ecklonia Cava Extract (enzyme extract; 3000 mg) was given to SD rats (5/sex) or Beagle dogs (2/sex) by oral gavage.92 The oral LD50s of two Fucus Vesiculosus Extracts were 1000 and 500 mg/kg for male mice and between 1000 and 2000 mg/kg and < 750 mg/kg for female mice.93 In rats (sex not stated), the oral LD50s of two Fucus Vesiculosus Extracts were between 1000 and 2000 mg/kg for one extract and > 2000 mg/kg for the second extract.93 The oral LD50 of rats given 20% of a test substance containing Laminaria Digitata Extract (≤ 10%), artemisia vulgaris extract (≤ 10%), and phenoxyethanol (0.8%), in water, was > 5000 mg/kg.94 Sargassum Fulvellum Extract and Sargassum Thunbergii Extract were not toxic to mice that were given a single dose of 5000 mg in 10 mL Tween-80 via gavage.50

Short-Term, Subchronic, and Chronic Toxicity Studies No repeated dose dermal or inhalation toxicity studies were discovered in the published literature, and no

unpublished data were submitted. Short-term, subchronic, and chronic oral toxicity studies summarized below are presented in Table 28. Oral

Ascophyllum Nodosum was not toxic when it was fed to pigs at up to 10% via feed for 23 days, or to rats at up to 15% in the diet for 4 weeks.45,95 Vomiting was the only adverse effect when Ecklonia Cava Extract in capsules was orally


administered (in increasing amounts up to 1000 mg/kg over 8 days) to dogs.9 Ecklonia Cava Extract was not toxic to rats dosed with up to 3000 mg/kg via oral gavage once daily in rats, and twice daily in dogs, for 13 weeks.9,92 An enzyme extract of Ecklonia Cava Extract (starting at doses of 2000 mg/kg) administered by gavage for 2 weeks caused reduced ovary and brain weights in female rats.92 Hepatic effects in rats were observed when animals were dosed with 2000 mg/kg/day via gavage of an alcohol Ecklonia Cava Extract for 4 weeks.9 While consuming high-fat diets, there were no adverse effects caused by alcohol Ecklonia Cava Extract when mice were given doses of up to 5 mg/day via gavage for 4 weeks.96 When rats were dosed with the same extract at doses of 1500 mg/kg/day for 13 weeks, there were also decreases in body weight gain and organ weights (the hepatic effects resolved after 4 weeks recovery).9

Increased liver weights were apparent when two ethanol Fucus Vesiculosus Extracts (starting at doses of 200 mg/kg/day) were administered by gavage for 4 weeks in male rats.93 No treatment-related effects were noted in females. An ethanol Laminaria Japonica Extract (up to 400 mg/kg) administered by gavage for 6 weeks caused decreased body weight gain, fat-pad weights, and serum and hepatic lipid levels in rats.46

In rats, doses of 1200 to 4000 mg/kg Cladosiphon Okamuranus Extract given once a day for 3 months via gavage caused a dose-dependent increase in clotting time and decrease in alkaline phosphatase (ALP) that was not observed with lower doses.47 There were no other adverse effects reported.

Laminaria Japonica Powder (up to 5%) was incorporated in the feed of mice from the age of 7 weeks until death. There were no dose-dependent effects on the lifespan of mice.48 Undaria Pinnatifida Extract administered via drinking water (1.5 g in 1000 mL water) did not cause any toxic effects in rats when administered for 32 weeks.97 Undaria Pinnatifida Powder (0.1, 1, or 5%) was given to 5 female SD rats for 36 weeks via diet.98 No adverse effects were reported.

DEVELOPMENTAL AND REPRODUCTIVE TOXICITY (DART) STUDIES

No DART studies were discovered in the published literature, and no unpublished data were submitted.

GENOTOXICITY STUDIES The in vitro and in vivo genotoxicity studies summarized below are presented in Table 29.

In Vitro Ascophyllum Nodosum Extract was not genotoxic in two Ames assays (up to 5000 µg/plate), a mammalian cell

gene mutation test (up to 500 µg/mL), or in chromosomal aberration assays (up to 5 mg/mL); in a mammalian cell gene mutation test, Ascophyllum Nodosum Extract was genotoxic to Chinese hamster ovary (CHO) cells starting at 1500 µg/mL.6,91 An Ames test was performed according to the Organisation for Economic Co-operation and Development (OECD) test guideline (TG) 471 on a trade name mixture containing 4.7% Ascophyllum Nodosum Extract in 94.5% water.70 No mutagenic activity was reported. Cystoseira Compressa Extract was not mutagenic in an Ames assay performed with and without metabolic activation at up to 5 mg/plate.62 Ecklonia Cava Extract was not genotoxic in Ames assays (up to 5000 µg/plate) or chromosomal aberration assays (up to 350 µg/plate).9,92 Halidrys Siliquosa Extract was non-mutagenic in an Ames assay, performed according to OECD TG 471, at up to 5 µL/plate.65 Another Ames assay performed according to OECD TG 471 resulted in negative results when testing the genotoxic potential of a mixture consisting of Fucus Spiralis Extract (12%), tetraselmis chui extract (8%), and water (80%) (up to 5 µL/plate). 99 Aqueous Fucus Vesiculosus Extract was not genotoxic in a chromosomal aberration assay (up to 1 mg/mL; human peripheral lymphocytes) or a comet assay (up to 1 mg/mL; human peripheral lymphocytes).100 Laminaria digitata was non-mutagenic in an ames assay performed with and without metabolic activation (concentrations not stated).101 A trade name mixture containing Laminaria Saccharina Extract in sea water and methylpropandiol was non-mutagenic in an Ames assay (up to 5000 µg/plate).102 Macrocystis Pyrifera (Kelp) Extract was non-mutagenic in an Ames assay (1 mL test substance in 10 mL 0.9% sodium chloride; concentration of extract was approximately 4%).103 A trade name mixture containing 24% Undaria Pinnatifida Cell Culture Extract was not mutagenic in a bacterial reverse mutation assay (up to 5000 µg/plate).104 No genotoxicity was reported in a chemiluminescent 3D assay using water (52%) and Cystoseira Amentacea/ Caespitosa/Brachycarpa Extract (48%) as the test substance at up to 10%.105 The test system for this study was not reported.

In Vivo

Ecklonia Cava Extract was not genotoxic in micronucleus assays up to 3000 mg/kg using male CD1 mice.9,92

CARCINOGENICITY STUDIES No carcinogenicity studies were discovered in the published literature, and no unpublished data were submitted.

Tumor Promotion Tumor promotion studies summarized below are presented in Table 30. The brown algae-derived ingredients that

were tested were not tumor promoters; instead, decreases in the number, incidence, and size of tumors in rats and mice were


observed.

Dermal Mice were treated dermally with a single dose of 7,12-dimethylbenz[a]anthracene (DMBA; a carcinogen) followed

by biweekly treatments for fifteen weeks with 12-O-tetradecanoylphorbol-13-acetate (TPA; a tumor promotor) or Undaria Pinnatifida Extract (1 mg).106 The mice treated with Undaria Pinnatifida Extract had a delayed appearance of skin tumors (14 vs 8 weeks) and fewer tumors (average 0.2 vs 3.7) compared to the TPA-treated mice.

Oral

Rats injected with azoxymethane (AOM; a carcinogen) and then fed a diet containing Hizikia Fusiforme Extract (2% and 6%) had a reduced number of colorectal tumors (21 vs 58) compared to rats injected with AOM and fed a normal diet.107 A Saccharina angustata powder (5%; inference for Saccharina Angustata Extract) in feed delayed the appearance and reduced the incidences of mammary tumors in rats orally administered DMBA.108

Rats administered N-methyl-N′-nitro-N-nitrosoguanidine (MNNG; a carcinogen) followed by Sargassum Pallidum Extract (0, 400, 600 and 800 mg/kg/day) in drinking water for 8 weeks had decreased inflammatory responses; serum IL-6, IL-1β, and TNF-α levels and concentration of serum and gastric mucosa malondialdehyde (MDA; an oxidant) were decreased in a dose-dependent manner.109 In rats administered Undaria Pinnatifida Powder (0, 1.0% or 5.0% in feed) for 8 weeks after oral administration of DMBA, the mean combined weight of all mammary tumors of each rat in treatment groups was lower than that in the control group (approximately 7 vs 20 g).98 Undaria Pinnatifida Extract (100% as drinking water) for 32 weeks reduced the incidence of mammary tumors (22% vs 100%) after female rats were orally administered DMBA.97

OTHER RELEVANT STUDIES

Endocrine Effects In Vitro Fucus vesiculosus extract

Human granulosa cells (obtained from 8 women) were treated with a water:ethanol (1:1) Fucus vesiculosus extract (25, 50, or 75 µmol/l) for 9 days.110 Ethanol (50%) served as the vehicle control. At 50 and 75 µmol/l, the extract significantly reduced 17-β-estradiol levels in human granulosa cells and also competed with estradiol (E2) and progesterone for binding to their receptors.

Affinity of this extract for estrogen receptor-α (ERα), ERβ, and progesterone receptor (PR)-B was determined by radiometric competitive binding assays.110 Dried extract (0.5, 5, or 50 µmol/l final concentration) was re-solubilized in dimethyl sulfoxide and combined with ERα or ERβ and 0.5 nmol/l estradiol. Non-specific binding was estimated in the presence of 1 µmol/l diethylstilbesterol. To test PR-B binding, the extract was incubated with PR-B and 1.4 nmol/l radiolabeled progesterone. Non-specific binding was estimated in the presence of 1 µmol/l progesterone. The extract competed for and bound to ERα (IC50 = 42.2 µmol/l), ERβ (IC50 = 31.8 µmol/l), and PR-B (IC50 = 31.8 µmol/l), with a slightly greater affinity for ERβ. The inhibition of progesterone production was less prominent, and there was no concentration-response relationship. In contrast, there was a concentration-dependent occupancy of the estrogen and progesterone receptors. Compounds found in Fucus vesiculosus could act as estradiol antagonists by decreasing the affinity of either ERα or ERβ for its ligand.

In competitive radio-ligand binding assays, aromatase activity was estimated by measuring the incorporation of tritium from androstenedione into water in the presence or absence of a Fucus vesiculosus extract (10, 50, or 100 µmol/L).110 Aromatase activity following treatment of human luteinized granulosa cells (hLGCs) with this extract did not change.

A chemically activated luciferase reporter (CALUX®) assay was used to determine the effect of an aqueous Fucus vesiculosus extract on activation of the ER.111 Aromatase enzymatic activity was measured to determine the potential effect of this extract on E2 biosynthesis. In co-treatments with E2, this extract (2%) reduced the activation of the luciferase reporter by up to 50%, exhibiting ER antagonistic effects. The effect of this extract (0 to 2%) on aromatase activity was measured using recombinant human CYP19 enzymatic hydrolysis of the fluorescent substrate, 7-methoxy-4-trifluoromethyl coumarin, in a 96-well plate. Ketoconazole was used as the positive marker of aromatase inhibition. This extract inhibited aromatase activity (IC50 2.0%). ER-dependent and -independent cancer cell lines showed significantly decreased viability with increasing Fucus vesiculosus extract concentrations; altered morphological features suggested apoptosis and autophagy. The cell line-specific sensitivity suggests that Fucus vesiculosus extract was not toxic at up to 2%, but instead induces cell death through modulated pathways.


Animal Fucus vesiculosus powder

Female Sprague-Dawley rats (n = 8), that had two confirmed normal estrous cycles, were administered a Fucus vesiculosus powder (0, 175, or 350 mg/kg/day) on an apple wedge daily for 4 weeks.110 Vaginal smears were obtained and daily logs were maintained to monitor estrous cycling. No adverse effects were observed during the course of the experiment. Administration of this powder resulted in a statistically-significant, dose-dependent increase in the length of the estrous cycle in the treated rats. In the control group, the mean number of days of the estrous cycle was 4.3 ± 0.96 days compared to 5.4 ± 1.7 days in the low-dose group and 5.9 ± 1.9 days in the high-dose group. Treatment with this powder caused an overall 100% increase in the mean length of the diestrus phase of the estrous cycle. The mean number of days in diestrus was 0.97 ± 0.22 among the controls compared to 1.4 ± 0.54 in the low-dose group and 2.1 ± 0.88 days in the high-dose group. Treatment had no significant effect on the number of days in estrus, proestrus, or metestrus during the mean estrous cycle. After treatment was stopped, five rats stopped normal estrous cycling; one remained in estrus and four in diestrus.

Blood samples were collected from female Sprague-Dawley rats (n = 19) before treatment with dried Fucus vesiculosus powder, and at 2 and 4 weeks of the oral administration of this powder (0 or 175 mg/kg/d) on apple wedges.110 At 2 weeks, mean serum 17β-estradiol levels were reduced from 48.9 ± 4.5 to 40.2 ± 3.2 ng/l and, after 4 weeks, reduced the levels from baseline to 36.7 ± 2.2 ng/l (25% decrease), suggesting an effect of dosing over time. Serum progesterone levels between controls and the treatment groups did not differ.

Blood samples were collected from female Sprague-Dawley rats (n = 8), that had naturally high circulating estradiol levels (≥ 50 µg/l), before, and after 1 week of the oral administration of Fucus vesiculosus powder (350 mg/kg/day) on apple wedges.110 Median serum 17-β-estradiol levels decreased by 38%. The range in reduction of serum 17-β-estradiol levels in 6 of the rats was 25% to 58%, whereas 2 rats had levels similar to their baseline levels. Progesterone levels were not significantly affected following this treatment. This could be due to the fact that in the studies with rats the blood samples were collected in the morning, and in the morning the 17-β-estradiol levels were at their peak but the progesterone levels were not.

Photoprotection

Sargassum muticum The effect of the ethyl acetate fraction of Sargassum muticum extract against cell death induced by mid-wavelength

ultraviolet (UVB) radiation was studied.112 Cells were seeded in a 96-well plate at a concentration of 1x10-5 cells/mL. Sixteen hours after plating, 100 µg/mL of Sargassum muticum extract were added to the cells and exposed to UVB radiation at a dose of 150 mJ/cm2. Cell viability was 61% in UVB (150 mJ/cm2) irradiated cells and 70% in UVB-irradiated cells treated with Sargassum muticum extract. Decreased numbers of apoptotic bodies as well as DNA fragmentation was apparent in cells exposed to Sargassum muticum extract and UVB, versus UVB exposure alone.

DERMAL IRRITATION AND SENSITIZATION STUDIES

The dermal irritation and sensitization studies summarized below are presented in Table 32.

Irritation

In Vitro In vitro dermal irritation assays were performed on a mixture containing 24% Undaria Pinnatifida Cell Culture

Extract in water; a mixture containing Laminaria Japonica (7%), Nereocystis Leutkeana (7%), Macrocystis Pyrifera Extract (7%), and pentaerythrityl tetraethylhexanoate; and a mixture containing Sargassum Filipendula Extract (1.3%), water (81.78%), sorbitol (14%), hypnea musciformis extract (1.4%), gellidiela acerosa extract (1.3%), methylparaben (0.2%), and propylparaben (0.2%).113,114,115 These trade name mixtures were considered to be non-irritating. Animal

Ascophyllum Nodosum Extract (4.7%; aqueous), Laminaria Digitata Extract (0.5 %) with dipropylene glycol and water or water and sea salt, and Laminaria Digitata Extract (0.5 %) with artemisia vulgaris extract, phenoxyethanol, and water, were non-irritating in animal dermal irritation studies.6,49,94,91 Human

Many human irritation studies were provided using test substances containing a brown algae ingredient, or combination of ingredients, along with other substances such as caprylic/capric triglycerides, butylene glycol, water, sea salt, propylene glycol, phenoxyethanol, panthenol, or dipropylene glycol. The majority of these studies resulted in negative results; however, irritation was seen in several studies after treatment with high concentrations or short periods of exposure.


In a study using a trade name mixture consisting of Fucus Spiralis Extract (< 5%) in caprylic/capric triglycerides as the test substance, slight irritation was observed after 30 minutes, however, no irritation was reported after 24 hours.116 A trade name mixture containing 20% Himanthalia Elongata Extract, 37% Undaria Pinnatifida Extract, and 43% water, was considered to be very slightly irritating to human skin.64 When a test substance consisting of Laminaria Digitata Extract (1.5 - 2.5%) in water and propylene glycol was applied to the skin, moderate irritation was observed after 30 minutes, and slight irritation was observed after 24 hours.117 In a different study, Laminaria Saccharina Extract (1 - 3%) in water and propylene glycol was applied at concentrations of 8, 16, and 100% to 10 subjects.118 Slight irritation was observed at the 100% dose level, and no irritation was observed at the lower doses. When a trade name mixture containing Pelvetia Canaliculata Extract (1 - 3%) in propylene glycol and water was applied to the skin, moderate irritation was noted after 30 minutes, and slight irritation was noted after 24 hours.119 Similar results were observed when a trade name mixture consisting of Undaria Pinnatifida Extract (< 5%) in water and propylene glycol was applied to the skin of 12 subjects.120 In a different study, the test substance (trade name mixture containing Pelvetia Canaliculata Extract and Laminaria Digitata Extract extracted in propylene glycol with panthenol (the amount of dry extract of both extracts combined is estimated to be 5.5 - 9.0%)) was applied to the skin of 10 subjects at concentrations of 5, 10, and 100%.121 Mild irritation was observed at the 100% concentration, minimal concentration was observed at the 10% concentration, and no irritation was reported at the 5% concentration.

Sensitization

In Vitro An ARE-Nfr2 Luciferase Test utilizing human keratinocyte cells at concentrations up to 2000 µM was performed to

study the sensitization potential of Undaria Pinnatifida Cell Culture Extract (24%).122 The test substance was non-sensitizing. A direct peptide reactivity assay (DPRA) performed testing the sensitizing potential of the same ingredient yielded negative results.123 An ARE-Nfr2 Luciferase Test was also performed on a trade name mixture containing Sargassum Filipendula Extract (1.3%), water (81.78%), sorbitol (14%), Hypnea Musciformis Extract (1.4%), gellidiela acerosa extract (1.3%), methylparaben (0.2%), and propylparaben (0.025%).123 No sensitization potential was observed.

Animal

Ascophyllum Nodosum Extract (25% - 75%), was non-sensitizing when applied to the skin of 20 guinea pigs.91 No sensitization was noted when a cream containing 0.0023% Cystoseira Amentacea/Caespitosa/Brachycarpa Extract was applied to 25 animals in a maximization test.124

Human All in vivo sensitization studies performed on humans, regarding several brown algae ingredients (Alaria Esculenta

Extract (0.5 - 2.5% and < 5%), Ascophyllum Nodosum Extract (0.5% - 75% ), Cystoseira Baccata Extract (0.5 – 10%), Cystoseira Tamariscifolia Extract (0.5 -10%), Dictyopteris Polypodioides Extract (0.5 – 10%), Fucus Spiralis (1 -3%), Fucus Vesiculosus Extract (5%), Halidrys Siliquosa Extract (48%), Halopteris Scoparia Extract (0.5 – 10%), Himanthalia Elongata Extract (0.2%), Macrocystis Pyrifera (Kelp) Extract (4%), Laminaria Digitata Extract (< 12%), Laminaria Saccharina Extract (< 3%), Pelvetia Canaliculata Extract (< 44%), Phyllacantha Fibrosa Extract (< 10%), Sphacelaria Scoparia Extract, Sargassum Filipendula Extract (1.2%), Sargassum Muticum Extract (0.076%), and Undaria Pinnatifida Extract (<5%)), were negative.49,65,94,103,116,124-129,129-141

Phototoxicity In Vitro Ascophyllum Nodosum Extract

A phototoxicity study was performed according to OECD TG 432 (3T3 NRU phototoxicity test) using a trade name mixture containing 4.7% Ascophyllum Nodosum Extract in 94.5% water.70 No additional details were provided. No phototoxic activity was reported.

OCULAR IRRITATION STUDIES

The studies summarized below are presented in Table 32. In Vitro

Many in vitro HET-CAM tests were performed. The majority of these tests resulted in no irritation or slight irritation; however, some studies resulted in moderate irritation. Macrocystis Pyrifera (Kelp) Extract was moderately irritating when used in a HET-CAM test.103 Moderate irritation was also noted when a cosmetic product consisting of Laminaria Ochroleuca Extract (5%), caprylic/capric triglycerides (94.75%), and tocopherols (0.25%), was used in a HET-CAM assay.142


Animal

Ascophyllum nodosum extract (100 mg; concentration not stated) was mildly irritating when applied ot the eyes of New Zealand White rabbits.6 In a different study performed according to OECD TG 405, Ascophyllum Nodosum Extract was slightly irritating.143 A test substance (diluted to 22% in water; 0.1 mL) containing Laminaria Digitata Extract (≤ 10%), artemisia vulgaris extract (≤ 10%), phenoxyethanol (0.8%), and water, was non-irritating when placed in the eyes of New Zealand White rabbits.94

Human

The ophthalmic irritation potential of an eye cream containing 0.076% Sargassum Muticum Extract was tested in 31 subjects, approximately 50% of which wore soft contact lenses.144 The test material did not indicate a potential for ophthalmologic irritation and was considered safe for use by both contact and non-contact lens wearers.

CLINICAL STUDIES Case Reports

Oral case reports regarding brown algae-derived supplements are presented in Table 33. Decreased platelet count and an increased amount of arsenic in the blood were noted in subjects taking kelp supplements. 145,146

Clinical Trials

Dermal

A gel formulation containing 1% of an aqueous extract of Fucus vesiculosus (0.2 mL) was tested in a double-blind, placebo-controlled experiment.44 Female subjects (n = 10) applied the gel to one cheek at least twice per day (morning and evening) for 5 weeks. The same gel, without the extract, was applied to the other cheek. The skin was examined before the experiment began, daily, and after the experiment ended. There were no signs of erythema or edema during the experiment.

Oral

Clinical trials summarized below are presented in Table 34. In an oral clinical trial in which an Ascophyllum nodosum powder (0.5g/d) was administered to healthy female

subjects, median urinary iodine concentrations increased from 78 mg/l to 140 mg/l, and thyroid-stimulating hormone (TSH) concentrations increased slightly, but remained within the normal range.147 There were no adverse events reported. Administration of an alcohol extract of Ecklonia cava (400 mg/day) to subjects with hypercholesterolaemia for 12 weeks did not have an effect on hematology, clinical chemistry, or urinalysis parameters; however, one instance (2.2%) each of nausea, dyspepsia, diarrhea, and alopecia were reported.9,148 A phlorotannin-rich extract of Ecklonia cava (0, 72, or 144 mg/day) was administered for 12 weeks to overweight patients in a randomized, double-blind study. Hematological and clinical chemistry did not reveal any adverse effects; the 144 mg/d group showed decreases in serum glucose and systolic blood pressure (SBP).9 No adverse effects were reported when Ecklonia Cava Extract (alcohol extract; 400 mg) was given to 40 overweight subjcts for 12 weeks.24 Administration of capsules containing a desalinated Undaria pinnatifida powder (average intake estimated to be 3.3 g per day) to hypertensive subjects for 8 weeks resulted in a decrease in the average SBP, diastolic blood pressure (DBP), and total cholesterol; adverse effects included two cases of indigestion and one case of diarrhea, both of which resolved quickly without treatment.67

Three pre-menopausal women with irregular menstrual cycles were administered a Fucus vesiculosus powder.149 Subject number 1 was 43 years old with hypermenorrhea, polymenorrhea, dysmenorrhea, luteal phase deficiency, and endometriosis. Subject number 2 was 42 years old with hypermenorrhea, polymenorrhea, and dysmenorrhea. Subject number 3 was 21 years old with hypermenorrhea, dysmenorrhea, and endometriosis. Menstrual cycles were tracked for three cycles and serum 17β-estradiol and progesterone levels were measured before treatment started. Then the women were administered this powder in capsules (700 mg/day) for two menstrual cycles. Serum 17-β-estradiol and progesterone levels were measured again. Subject 2 stopped treatment at this point and subjects 1 and 3 continued treatment with a greater dose of this powder (1400 mg/day) for two more cycles. This powder increased the menstrual cycle length and reduced the days of menstruation in a dose-dependent manner (Table 35). In subject 1, the plasma estradiol levels were decreased (before: 626 ± 91 pg/mL; low dose: 164 ± 30 pg/mL; high dose: 92.5 ± 3.5 pg/mL) and the progesterone levels were increased (before: 0.58 ± 0.14 ng/mL; low-dose: 8.4 ± 2.6 ng/mL; high-dose: 16.8 ±0.7 ng/mL).149


SUMMARY This is a review of the safety of 82 brown algae-derived ingredients; however, several of these ingredients may be

equivalent according to accepted scientific names. Accordingly, the number of distinct cosmetic ingredients is 74. The ingredients in this review are extracts, powders, juices, or waters derived from one or multiple species of brown algae and may be derived from the whole or a defined part of the seaweed. “Brown algae” is a common name for seaweeds of the class Phaeophyceae, which have an abundance of xanthophyll pigments and are a known source of alginate. The most frequently reported function of brown algae ingredients in cosmetics is as a skin-conditioning agent; other reported functions include absorbent, antioxidant, binder, hair conditioning agent, oxidizing agent, and viscosity increasing agent.

Extraction methods and solvents vary, depending on the desired composition of the final ingredient. Powders, however, are generally the dried algae pulverized by milling. Arsenic, usually in the form of arsenosugars, is a natural constituent of brown algae and the amount in harvested algae can be reduced by several methods. In addition to arsenic, brown algae exhibit an affinity for heavy metals and uptake is strongly dependent on environmental parameters.

According to VCRP data received in 2019, Laminaria Digitata Extract is reported to be used in 310 formulations (229 in leave-on formulations, 74 in rinse-off formulations, and 7 diluted for the bath; Table 23).75 Fucus Vesiculosus Extract is reported to be used in 291 formulations, Macrocystis Pyrifera (Kelp) Extract in 199 formulations, and Ascophyllum Nodosum Extract is used in 140 formulations. The results of the concentration of use surveys conducted by the Council in 2015 and 2016 indicate Laminaria Digitata Powder has the highest reported maximum concentration of use; it is used at up to 40% in face and neck formulations. Macrocystis Pyrifera (Kelp) Extract is reported to be used at up to 36.4% in eye lotions. The rest of these ingredients are reported to be used at 6% or less.

According to the US FDA, brown algae (i.e., several species of seaweeds that are harvested principally in coastal waters of the northern Atlantic and Pacific oceans) are direct food substances that are GRAS for human consumption for use as flavor enhancers and flavor adjuvants, when the maximum level in food does not exceed the cGMP). “Kelp” (the dehydrated, ground product prepared from Macrocystis pyrifera, Laminaria digitata, Laminaria saccharina, and Laminaria cloustoni) is approved as a food additive for direct addition to food for human consumption as a source of iodine or as a dietary supplement. In animal drugs, feeds, and related products, brown algae (kelp; Laminaria spp. and Nereocystis spp.) are GRAS as natural substances and as solvent-free natural extractives used in conjunction with spices and other natural seasonings and flavorings.

Acute oral administration of brown algae extracts was not toxic to mice, rats, and dogs. The LD50 was reported to be > 2000 mg/kg when Sprague-Dawley rats were given Ascophyllum Nodosum extract. Cystoseira Compressa Extract was not toxic to mice up to 2000 mg/kg by gavage. Ecklonia Cava Extract was not toxic to rats and dogs up to 3000 mg/kg by gavage. The oral LD50s of two different Fucus Vesiculosus Extracts were 500 mg/kg and greater for mice and rats. Sargassum Fulvellum Extract and Sargassum Thunbergii Extract administered by gavage were not toxic to mice. The oral LD50 of rats given 20% of a test substance containing Laminaria Digitata Extract (≤ 10%), artemisia vulgaris extract (≤ 10%), and phenoxyethanol (0.8%), in water, was > 5000 mg/kg.

In oral short-term and subchronic studies, there were some adverse effects observed. In rats, Cladosiphon Okamuranus Extract (1200 to 4000 mg/kg by gavage) caused a dose-dependent increase in clotting time and decrease in ALP; there were no other adverse effects reported. An enzyme extract of Ecklonia Cava Extract (starting at 2000 mg/kg) administered by gavage for 2 weeks caused reduced ovary and brain weights in female rats. Hepatic effects in rats were observed when animals were treated with an alcohol Ecklonia Cava Extract at 2000 mg/kg/day for 4 weeks and at 1500 mg/kg/day for 13 weeks (the hepatic effects resolved after 4 weeks of recovery). There were increased liver weights in male rats treated with two ethanol Fucus Vesiculosus Extracts (starting at 200 mg/kg/day) administered by gavage for 4 weeks. Vomiting was the only adverse effect when Ecklonia Cava Extract capsules (in increasing amounts up to 1000 mg/kg over 8 days) were orally administered to dogs.

In other oral short-term and subchronic studies, there were no adverse effects observed. Ascophyllum Nodosum was not toxic to pigs for 23 days or to rats for 4 weeks administered in feed at up to 10% and 15%, respectively. While consuming high-fat diets, there were no adverse effects caused by alcohol Ecklonia Cava Extract (up to 5 mg/day) administered to mice by gavage daily for 4 weeks and an ethanol Laminaria Japonica Extract (up to 400 mg/kg) administered by gavage for 6 weeks caused decreased body weight gain, fat-pad weights, and serum and hepatic lipid levels in rats. An Ecklonia cava powder (up to 0.15%; inference for Ecklonia Cava Extract and Ecklonia Cava Water) administered in feed for 28 days was not toxic to weanling pigs.

In a chronic oral toxicity study, the NOAEL of a Laminaria Japonica Extract administered to rats by gavage for 6 months was 300 mg/kg/day. In females, a decrease in AST was observed starting at 300 mg/kg/day and, at 2500 mg/kg/day, there was decreased serum glucose concentration; all effects returned to baseline after a 1-month recovery. Laminaria Japonica Powder incorporated into feed did not affect the lifespan of mice at up to 5%. In rats, Undaria Pinnatifida Extract administered as drinking water at a concentration of 1.5 g/L for 32 weeks and incorporated into the feed (at up to 5%) for 36 weeks did not cause any toxic effects.

In genotoxicity assays of several of the brown algae-derived ingredients, all results were negative with the exception of an Ascophyllum Nodosum Extract in one mammalian cell gene mutation test in which the extract was genotoxic starting at 1500 µg/mL in CHO cells. With metabolic activation, Ascophyllum Nodosum Extract was not genotoxic in CHO cells.


Ascophyllum Nodosum Extract was not genotoxic in two Ames assays and a mammalian cell gene mutation test (up to 500 µg/mL), and in chromosome aberration assays (up to 5 mg/mL). Cystoseira Compressa Extract (up to 5 mg/plate) was not genotoxic in an Ames assay. Ecklonia Cava Extract was not genotoxic in Ames assays (up to 5000 µg/plate) and chromosome aberration assays (up to 350 µg/plate). Fucus Spiralis Extract in water and tetraselmis chui extract was non-genotoxic in an Ames assay (up to 5 µg/plate). Aqueous Fucus Vesiculosus Extract was not genotoxic in a chromosome aberration assay and a comet assay (up to 1 mg/mL). Halidrys Siliquosa Extract was non-mutagenic in an Ames assay (up to 5 µL/plate). Laminaria Japonica Extract (up to 5000 µg/plate) was not mutagenic in an Ames assay and a chromosome aberration assay. Macrocystis Pyrifera (Kelp) Extract was non-mutagenic in an Ames assay (1 mL test substance in 10 mL 0.9% sodium chloride; concentration of extract not provided). Undaria Pinnatifida Extract was not genotoxic in Ames assays and chromosome aberration assays (up to 5000 µg/mL). In a micronucleus assay, Ecklonia Cava Extract (up to 3000 mg/kg), was not genotoxic. An Ames test performed using a trade name mixture containing Laminaria Saccharina Extract in sea water and methylpropandiol at up to 5000 µg/plate resulted in negative results. A different Ames test was performed according to OECD TG 471 using a trade name mixture containing 4.7% Ascophyllum Nodosum Extract in 94.5% water. No mutagenic activity was reported. In a bacterial reverse mutation assay performed according to OECD TG 471, a trade name mixture containing 24% Undaria Pinnatifida Extract was not mutagenic (up to 5000 µg/plate). No genotoxicity was reported in a chemiluminescent 3D assay using water 52% and Cystoseira Amentacea/Caespitosa/ Brachycarpa Extract (48%) as the test substance.

None of the orally or dermally administered brown algae-derived ingredients tested (e.g., Hizikia Fusiforme Extract, Saccharina Angustata Extract (inference from Saccharina angustata powder), Undaria Pinnatifida Extract, and Undaria Pinnatifida Powder) were tumor (mammary and colorectal) promoters; instead, decreases in the number, incidence, and/or size of tumors in rats were reported. Rats administered MNNG followed by 8 weeks of Sargassum Pallidum Extract (400 to 800 mg/kg/day) in drinking water exhibited decreased inflammatory responses.

A Fucus vesiculosus extract exhibited estrogen effects in several in vitro studies. This extract (50 and 75 µmol/l) reduced 17-β-estradiol levels in human granulosa cells and also competed with estradiol and progesterone for binding to the respective receptors. In another study, a Fucus vesiculosus extract competed for, and bound to, ERα (IC50 = 42.2 µmol/l), ERβ (IC50 = 31.8 µmol/l), and PR-B (IC50 = 31.8 µmol/l), with a slightly higher affinity for ERβ. In co-treatments with E2 (12.5 pM; EC50), a Fucus vesiculosus extract (2%) reduced the activation of the luciferase reporter by up to 50%, exhibiting ER antagonistic effects. ER-dependent and -independent cancer cell lines showed significantly decreased viability with increasing test material concentrations. The cell line-specific sensitivity suggests that Fucus vesiculosus extract was not toxic at up to 2%, but instead induces cell death through modulated pathways. In one study, aromatase activity following treatment of hLGCs with a Fucus vesiculosus extract (10 to 100 µmol/L) did not change.

In in vivo studies, a Fucus vesiculosus powder exhibited estrogenic effects. Oral administration (175 and 350 mg/kg/day) for 4 weeks resulted in a dose-dependent increase in the length of the estrous cycle and an overall 100% increase in the mean length of the diestrus phase of the estrous cycle in the treated rats. Mean serum 17-β-estradiol levels were reduced at 2 weeks and further reduced at 4 weeks. Female rats that had naturally high circulating estradiol had reduced serum 17-β-estradiol (25% to 58% in 2/8 rats) after 1 week oral administration of a Fucus vesiculosus powder (350 mg/kg/day). This powder (700 and 1400 mg/day) increased the menstrual cycle length and reduced the days of menstruation in a dose-dependent manner in three female human subjects with hypermenorrhea, dysmenorrhea, and other related ailments. In one subject, the plasma estradiol levels were decreased and the progesterone levels were increased in a dose-dependent manner.

In an in vitro study examining the photo-protection potential involving a Sargassum muticum extract, the effect of this extract against cell death induced by UVB radiation was studied. Cell viability was 61% in UVB (150 mJ/cm2) irradiated cells and 70% in UVB-irradiated cells treated with Sargassum muticum exract. Decreased numbers of apoptotic bodies as well as DNA fragmentation was apparent in cells exposed to Sargassum muticum extract and UVB versus UVB exposure alone.

In vitro dermal irritation assays were performed on a mixture containing 24% Undaria Pinnatifida Cell Culture Extract in water; a mixture containing Laminaria Japonica (7%), Nereocystis Leutkeana (7%), Macrocystis Pyrifera Extract (7%), and pentaerythrityl tetraethylhexanoate; and a mixture containing Sargassum Filipendula Extract (1.3%), water (81.78%), sorbitol (14%), hypnea musciformis extract (1.4%), gellidiela acerosa extract (1.3%), methylparaben (0.2%), and propylparaben (0.2%). These trade name mixtures were considered to be non-irritating.

Ascophyllum Nodosum Extract (4.7%), Laminaria Digitata Extract (0.5%) with dipropylene glycol and water or water and sea salt, and Laminaria Digitata Extract (0.5%) with artemisia vulgaris extract, phenoxyethanol, and water, were non-irritating in animal dermal irritation studies. Many human irritation studies were provided using test substances containing a brown algae ingredient, or combination of ingredients, along with other substances such as caprylic/capric triglycerides, butylene glycol, water, sea salt, propylene glycol, phenoxyethanol, panthenol, or dipropylene glycol. The majority of these studies resulted in negative results; however, irritation was seen in several studies after treatment with high concentrations or short periods of exposure. In a study using a trade name mixture consisting of Fucus Spiralis Extract (< 5%) in caprylic/capric triglycerides as the test substance, slight irritation was observed after 30 minutes, however, no irritation was reported after 24 hours. A trade name mixture containing 20% Himanthalia Elongata Extract, 37% Undaria Pinnatifida Extract, and 43% water, was considered to be very slightly irritating to human skin. When a test substance


consisting of Laminaria Digitata Extract (1.5 - 2.5%) in water and propylene glycol was applied to the skin, moderate irritation was observed after 30 minutes, and slight irritation was observed after 24 hours. In a different study, Laminaria Saccharina Extract (1 - 3%) in water and propylene glycol was applied at concentrations of 8, 16, and 100% to 10 subjects. Slight irritation was observed at the 100% dose level, and no irritation was observed at the lower doses. When a trade name mixture containing Pelvetia Canaliculata Extract (1 - 3%) in propylene glycol and water was applied to the skin, moderate irritation was noted after 30 minutes, and slight irritation was noted after 24 hours. Similar results were observed when a trade name mixture consisting of Undaria Pinnatifida Extract (< 5%) in water and propylene glycol was applied to the skin of 12 subjects. In a different study, the test substance (trade name mixture containing Pelvetia Canaliculata Extract and Laminaria Digitata Extract extracted in propylene glycol with panthenol (the amount of dry extract of both extracts combined is estimated to be 5.5 - 9.0%)) was applied to the skin of 10 subjects at concentrations of 5, 10, and 100%. Mild irritation was observed at the 100% concentration, minimal concentration was observed at the 10% concentration, and no irritation was reported at the 5% concentration.

An ARE-Nfr2 Luciferase Test utilizing human keratinocyte cells at concentrations up to 2000 µM was performed to study the sensitization potential of Undaria Pinnatifida Cell Culture Extract (24%) The test substance was considered to be non-sensitizing. A DPRA performed testing the sensitizing potential of the same ingredient yielded negative results. An ARE-Nfr2 Luciferase Test was also performed on a trade name mixture containing Sargassum Filipendula Extract (1.3%), water (81.78%), sorbitol (14%), Hypnea Musciformis Extract (1.4%), gellidiela acerosa extract (1.3%), methylparaben (0.2%), and propylparaben (0.025%). No sensitization potential was observed. Ascophyllum Nodosum Extract (25% - 75%), was non-sensitizing when applied to the skin of 20 guinea pigs. No sensitization was noted when a cream containing 0.0023% Cystoseira Amentacea/Caespitosa/Brachycarpa Extract was applied to 25 animals in a maximization test. All in vivo sensitization studies performed on humans, regarding several brown algae ingredients (Alaria Esculenta Extract (0.5 - 2.5% and < 5%), Ascophyllum Nodosum Extract (0.5% - 75% ), Cystoseira Tamariscifolia Extract (0.5 -10%), Dictyopteris Polypodioides Extract (0.5 – 10%), Fucus Spiralis (1 -3%), Fucus Vesiculosus Extract (5%), Halidrys Siliquosa Extract (48%), Halopteris Scoparia Extract (0.5 – 10%), Himanthalia Elongata Extract (0.2%), Macrocystis Pyrifera (Kelp) Extract (4%), Laminaria Digitata Extract (< 12%), Laminaria Saccharina Extract (< 3%), Pelvetia Canaliculata Extract (< 44%), Phyllacantha Fibrosa Extract (< 10%), Sphacelaria Scoparia Extract, Sargassum Filipendula Extract (1.2%), Sargassum Muticum Extract (0.076%), and Undaria Pinnatifida Extract (<5%)), were negative.

A phototoxicity study was performed according to OECD TG 432 using a trade name mixture containing 4.7% Ascophyllum Nodosum Extract in 94.5% water. No phototoxic activity was reported.

Many in vitro HET-CAM tests were performed. The majority of these tests resulted in no irritation or slight irritation; however, some studies resulted in moderate irritation. Macrocystis Pyrifera (Kelp) Extract was moderately irritating when used in a HET-CAM test. Moderate irritation was also noted when a cosmetic product consisting of Laminaria Ochroleuca Extract (5%), caprylic/capric triglycerides (94.75%), and tocopherols (0.25%), was used in a HET-CAM assay.

An Ascophyllum nodosum extract (100 mg) administered to the eyes of rabbits had a maximum irritation score of 6.7 out of 8 at 1 h post-instillation. The score decreased to 0 by day 7 and was rated as a mild ocular irritant. Ascophyllum Nodosum Extract was slightly irritating in an ocular irritation study performed according to OECD TG 405. No other details were provided for this study. The ophthalmic irritation potential of an eye cream containing 0.076% Sargassum Muticum Extract was tested in 31 subjects. The test material did not indicate a potential for ophthalmologic irritation and was considered safe for use by both contact and non-contact lens wearers. A test substance diluted to 20% containing Laminaria Digitata Extract (≤ 10%), artemisia vulgaris extract (≤ 10%), phenoxyethanol (0.8%), and water was considered non-irritating when placed in the eyes of New Zealand White rabbits.

No signs of edema or erythema were noted when a gel formulation containing 1% of an aqueous extract of Fucus vesiculosus (0.2 mL) was applied to the cheeks of 10 female subjects. In oral human clinical trials, adverse effects of an Ascophyllum nodosum powder (0.5 g/d), an Ecklonia cava extract (up to 400 mg/day), and an Undaria pinnatifida powder (average intake 3.3 g/d) were mild and transient. The adverse effects included nausea, indigestion, dyspepsia, and diarrhea.

DISCUSSION

The Panel reviewed the ingredients in this report and concluded that 6 of the 82 ingredients are safe as used in cosmetics in the present practices of use, while the remaining ingredients had insufficient data to issue a safety conclusion. The ingredients that are considered safe were given this status due to availability of systemic toxicity data, via either a GRAS status or oral exposure data, and sensitization data. Those ingredients that were considered insufficient did not meet these two requirements, therefore, in order to issue a safety conclusion for these ingredients, both systemic toxicity and sensitization data are required.

The Panel noted an elevated amount of heavy metals and arsenic, which may be present in these brown algae-derived ingredients. They stressed that the cosmetics industry should continue to use cGMPs to limit these impurities. In addition, possible estrogenic effects were noted, however, the concern for these effects were mitigated as they were only seen at concentrations much higher than what would be used in cosmetics. Clinical studies suggesting the toxic potential of


iodine via brown algae consumption as a dietary supplement were noted. However, the systemic exposure to iodine via the use of brown algae ingredients in cosmetics would be far less than that resulting from ingestion.

The Panel discussed the issue of incidental inhalation exposure from formulations that may be aerosolized (e.g., face/neck products at up to 0.79% (Macrocystis Pyrifera (Kelp) Extract). The Panel noted that in aerosol products, 95% – 99% of droplets/particles would not be respirable to any appreciable amount. Furthermore, droplets/particles deposited in the nasopharyngeal or bronchial regions of the respiratory tract present no toxicological concerns based on the chemical and biological properties of these ingredients. Coupled with the small actual exposure in the breathing zone and the concentrations at which the ingredients are used, the available information indicates that incidental inhalation would not be a significant route of exposure that might lead to local respiratory or systemic effects. A detailed discussion and summary of the Panel’s approach to evaluating incidental inhalation exposures to ingredients in cosmetic products is available at https://www.cir-safety.org/cir-findings.

In addition to the requested systemic toxicity data and sensitization data for all ingredients that are lacking these data, the Panel has requested data regarding the possible constituents of concern of these brown-algae derived ingredients (e.g., specific terpenoids and flavonoids, and concentrations of such). As an alternative, the Panel suggested obtaining representative data for each genus, which may be used to formulate decisions regarding other ingredients of the same genus.

CONCLUSION

The CIR Expert Panel concluded that the following 6 of the 82 reviewed brown algae-derived ingredients are safe in cosmetics in the present practices of use and concentration described in this safety assessment.

Alaria Esculenta Extract Laminaria Digitata Extract Laminaria Saccharina Extract

Macrocystis Pyrifera (Kelp) Extract Undaria Pinnatifida Extract Undaria Pinnatifida Cell Culture Extract*

*Not reported to be in current use. Were this ingredient not in current use to be used in the future, the expectation is

that it would be used in product categories and at concentrations comparable to others in this group. The CIR Expert Panel also concluded that the available data are insufficient to make a determination that the

remaining 76 ingredients are safe under the intended conditions of use in cosmetic formulations.

Agarum Cribrosum Extract Ascophyllum Nodosum** Ascophyllum Nodosum Extract Ascophyllum Nodosum Powder Cladosiphon Novae-Caledoniae

Extract** Cladosiphon Okamuranus Extract Cystoseira Amentacea/Caespitosa/

Branchycarpa Extract** Cystoseira Baccata Extract** Cystoseira Balearica Extract* Cystoseira Caespitosa Extract* Cystoseira Compressa Extract** Cystoseira Compressa Powder** Cystoseira Tamariscifolia Extract** Dictyopteris Polypodioides Extract Dictyota Coriacea Extract** Durvillaea Antarctica Extract Ecklonia Cava Extract** Ecklonia Cava Water** Ecklonia Kurome Extract** Ecklonia Kurome Powder** Ecklonia/Laminaria Extract** Ecklonia Maxima Extract** Ecklonia Maxima Powder** Ecklonia Radiata Extract Eisenia Arborea Extract** Fucus Serratus Extract

Fucus Spiralis Extract** Fucus Vesiculosus Fucus Vesiculosus Extract Fucus Vesiculosus Powder Halidrys Siliquosa Extract** Halopteris Scoparia Extract Himanthalia Elongata Extract Himanthalia Elongata Powder** Hizikia Fusiforme Extract* Hizikia Fusiformis Water* Hizikia Fusiformis Callus Culture

Extract** Hydrolyzed Ecklonia Cava Extract** Hydrolyzed Fucus Vesiculosus

Extract** Hydrolyzed Fucus Vesiculosus

Protein** Laminaria Cloustoni Extract Laminaria Diabolica Extract** Laminaria Digitata Powder Laminaria Hyperborea Extract Laminaria Japonica Extract Laminaria Japonica Powder** Laminaria Longissima Extract** Laminaria Ochroleuca Extract Lessonia Nigrescens Extract Lessonia Nigrescens Powder** Macrocystis Pyrifera (Kelp)

Macrocystis Pyrifera (Kelp) Blade/ Pneumatocyst/Stipe Juice Extract**

Macrocystis Pyrifera (Kelp) Juice** Macrocystis Pyrifera (Kelp) Protein Nereocystis Luetkeana Extract Pelvetia Canaliculata Extract Pelvetia Siliquosa Extract** Phyllacantha Fibrosa Extract** Saccharina Angustata Extract** Saccharina Japonica Extract** Saccharina Longicruris Extract Sargassum Filipendula Extract Sargassum Fulvellum Extract Sargassum Fusiforme Extract Sargassum Glaucescens Extract** Sargassum Horneri Extract** Sargassum Muticum Extract Sargassum Pallidum Extract** Sargassum Siliquastrum Extract** Sargassum Thunbergii Extract** Sargassum Vulgare Extract Sphacelaria Scoparia Extract Undaria Peterseniana Extract** Undaria Pinnatifida Leaf/Stem Extract** Undaria Pinnatifida Powder Undaria Pinnatifida Root Powder**

**Not reported to be in current use.


https://www.cir-safety.org/cir-findings

Ingredients in green type have sufficient systemic toxicity data, however, sensitization data are insufficient to determine safety. Ingredients in blue type have sufficient sensitization data, however, systemic toxicity data are insufficient to determine safety. Ingredients in black type have insufficient systemic toxicity and sensitization data.


TABLES Table 1. Brown algae INCI names Agarum Cribrosum Extract Alaria Esculenta Extract Ascophyllum Nodosum Ascophyllum Nodosum Extract Ascophyllum Nodosum Powder Cladosiphon Novae-Caledoniae Extract Cladosiphon Okamuranus Extract Cystoseira Amentacea/Caespitosa/ Branchycarpa Extract Cystoseira Baccata Extract (equivalent to Phyllacantha Fibrosa Extract) Cystoseira Balearica Extract (equivalent to Cystoseira Caespitosa Extract) Cystoseira Caespitosa Extract (equivalent to Cystoseira Balearica Extract) Cystoseira Compressa Extract Cystoseira Compressa Powder Cystoseira Tamariscifolia Extract Dictyopteris Polypodioides Extract Dictyota Coriacea Extract Durvillaea Antarctica Extract Ecklonia Cava Extract Ecklonia Cava Water Ecklonia Kurome Extract Ecklonia Kurome Powder Ecklonia/Laminaria Extract Ecklonia Maxima Extract Ecklonia Maxima Powder Ecklonia Radiata Extract Eisenia Arborea Extract Fucus Serratus Extract Fucus Spiralis Extract Fucus Vesiculosus Fucus Vesiculosus Extract Fucus Vesiculosus Powder Halidrys Siliquosa Extract

Halopteris Scoparia Extract (equivalent to Sphacelaria Scoparia Extract) Himanthalia Elongata Extract Himanthalia Elongata Powder Hizikia Fusiforme Extract (equivalent to Sargassum Fusiforme Extract) Hizikia Fusiformis Water Hizikia Fusiformis Callus Culture Extract Hydrolyzed Ecklonia Cava Extract Hydrolyzed Fucus Vesiculosus Extract Hydrolyzed Fucus Vesiculosus Protein Laminaria Cloustoni Extract (equivalent to Laminaria Hyperborea Extract) Laminaria Diabolica Extract (equivalent to Laminaria Japonica Extract; Laminaria Ochroleuca Extract; and Saccharina Japonica Extract) Laminaria Digitata Extract Laminaria Digitata Powder Laminaria Hyperborea Extract (equivalent to Laminaria Cloustoni Extract) Laminaria Japonica Extract (equivalent to Laminaria Diabolica Extract; Laminaria Ochroleuca Extract; and Saccharina Japonica Extract) Laminaria Japonica Powder Laminaria Longissima Extract Laminaria Ochroleuca Extract (equivalent to Laminaria Diabolica Extract; Laminaria Japonica Extract; and Saccharina Japonica Extract) Laminaria Saccharina Extract Lessonia Nigrescens Extract Lessonia Nigrescens Powder Macrocystis Pyrifera (Kelp)

Macrocystis Pyrifera (Kelp) Blade/Pneumatocyst/Stipe Juice Extract Macrocystis Pyrifera (Kelp) Extract Macrocystis Pyrifera (Kelp) Juice Macrocystis Pyrifera (Kelp) Protein Nereocystis Luetkeana Extract Pelvetia Canaliculata Extract Pelvetia Siliquosa Extract Phyllacantha Fibrosa Extract (equivalent to Cystoseira Baccata Extract) Saccharina Angustata Extract Saccharina Japonica Extract (equivalent to Laminaria Diabolica Extract; Laminaria Japonica Extract; and Laminaria Ochroleuca Extract) Saccharina Longicruris Extract Sargassum Filipendula Extract Sargassum Fulvellum Extract Sargassum Fusiforme Extract (equivalent to Hizikia Fusiforme Extract) Sargassum Glaucescens Extract Sargassum Horneri Extract Sargassum Muticum Extract Sargassum Pallidum Extract Sargassum Siliquastrum Extract Sargassum Thunbergii Extract Sargassum Vulgare Extract Sphacelaria Scoparia Extract (equivalent to Halopteris Scoparia Extract) Undaria Peterseniana Extract Undaria Pinnatifida Extract Undaria Pinnatifida Cell Culture Extract Undaria Pinnatifida Leaf/Stem Extract Undaria Pinnatifida Powder Undaria Pinnatifida Root Powder

Table 2. Current and retired INCI names, definitions, and functions of the brown algae-derived ingredients in this safety assessment1 Ingredient Definition Function Agarum Cribrosum Extract Agarum Cribrosum Extract is the extract of the alga, Agarum cribrosum. Skin-conditioning agent -

miscellaneous Alaria Esculenta Extract Alaria Esculenta Extract is the extract of the alga, Alaria esculenta. Hair conditioning agent; skin

protectant Ascophyllum Nodosum Ascophyllum Nodosum is the alga, Ascophyllum nodosum. Skin-conditioning agent -

miscellaneous Ascophyllum Nodosum Extract 84775-78-0

Ascophyllum Nodosum Extract is the extract of the alga, Ascophyllum nodosum.

Skin-conditioning agent - miscellaneous

Ascophyllum Nodosum Powder

Ascophyllum Nodosum Powder is the powder obtained from the dried, ground alga, Ascophyllum nodosum.


Cladosiphon Novae-Caledoniae Extract Cladosiphon Novae-Caledoniae Extract is the extract of the alga, Cladosiphon novae-caledoniae.

Humectant; skin protectant

Cladosiphon Okamuranus Extract Cladosiphon Okamuranus Extract is the extract of the alga, Cladosiphon okamuranus.


Cystoseira Amentacea/Caespitosa/ Branchycarpa Extract

Cystoseira Amentacea/Caespitosa/Branchycarpa Extract is the extract of the algae, Cystoseira amentacea, Cystoseira caespitosa, and Cystoseira branchycarpa.


Cystoseira Baccata Extract

Cystoseira Baccata Extract is the extract of the alga, Cystoseira baccata. Skin-conditioning agent - miscellaneous

Phyllacantha Fibrosa Extract Phyllacantha Fibrosa Extract is the extract of the alga, Phyllacantha fibrosa. The accepted scientific name for Phyllacantha fibrosa is Cystoseira baccata.



Table 2. Current and retired INCI names, definitions, and functions of the brown algae-derived ingredients in this safety assessment1 Ingredient Definition Function Cystoseira Balearica Extract Cystoseira Balearica Extract is the extract of the alga, Cystoseira balearica.

The accepted scientific name for Cystoseira balearica is Cystoseira brachycarpa.


Cystoseira Caespitosa Extract Cystoseira Caespitosa Extract is the extract of the alga, Cystoseira caespitosa. The accepted scientific name for Cystoseira caespitosa is Cystoseira brachycarpa.

Skin protectant

Cystoseira Caespitosa Extract See Cystoseira Balearica Extract. Cystoseira Compressa Extract Cystoseira Compressa Extract is the extract of the alga, Cystoseira

compressa. Skin-conditioning agent - miscellaneous

Cystoseira Compressa Powder Cystoseira Compressa Powder is the dried, ground powder obtained from the alga, Cystoseira compressa.


Cystoseira Tamariscifolia Extract Cystoseira Tamariscifolia Extract is the extract of the alga, Cystoseira tamarisfolia.


Dictyopteris Polypodioides Extract Dictyopteris Polypodioides Extract is the extract of the alga, Dictyopteris polypodioides.

Skin-conditioning agent – emollient; skin-conditioning agent - miscellaneous

Dictyopteris Membranacea Extract (Retired)

Dictyopteris Membranacea Extract (Retired) is the extract of the alga, Dictyopteris membranacea. The INCI Name, Dictyopteris Membranacea Extract, originally published in 2007, was designated with a retired status in 2015. For an interim period of time, trade name assignments formerly published with the INCI Name Dictyopteris Membranacea Extract will be retained in the retired monograph, and also published with the new name assignment based on the current genus and species name, Dictyopteris Polypodioides Extract.

Antioxidant

Dictyota Coriacea Extract Dictyota Coriacea Extract is the extract of the alga, Dictyota coriacea. Oxidizing agent Durvillaea Antarctica Extract Durvillaea Antarctica Extract is the extract of the alga, Durvillaea

antarctica. Skin-conditioning agent - miscellaneous

Ecklonia Cava Extract Ecklonia Cava Extract is the extract of the alga, Ecklonia cava. Humectant; skin-conditioning agent - humectant

Ecklonia Cava Water Ecklonia Cava Water is the aqueous solution of the steam distillates obtained from the alga, Ecklonia cava.

Skin protectant

Ecklonia Kurome Extract Ecklonia Kurome Extract is the extract of the alga, Ecklonia kurome. Skin-conditioning agent – humectant; skin-conditioning agent - miscellaneous

Ecklonia Kurome Powder Ecklonia Kurome Powder is the powder obtained from the dried, ground alga, Ecklonia kurome.

Skin-conditioning agent - humectant

Ecklonia/Laminaria Extract Ecklonia/Laminaria Extract is the extract of a mixture of the algae, Ecklonia and Laminaria.


Ecklonia Maxima Extract Ecklonia Maxima Extract is the extract of the alga, Ecklonia maxima. Skin-conditioning agent - miscellaneous

Ecklonia Maxima Powder Ecklonia Maxima Powder is the powder obtained from the dried, ground alga, Ecklonia maxima.


Ecklonia Radiata Extract Ecklonia Radiata Extract is the extract of the alga, Ecklonia radiata. Hair conditioning agent; skin-conditioning agent - miscellaneous

Eisenia Arborea Extract Eisenia Arborea Extract is the extract of the alga, Eisenia arborea. Skin-conditioning agent - miscellaneous

Fucus Serratus Extract 94167-02-9

Fucus Serratus Extract is the extract of the alga, Fucus serratus. Skin-conditioning agent - miscellaneous

Fucus Spiralis Extract Fucus Spiralis Extract is the extract of the alga, Fucus spiralis. Skin-conditioning agent – emollient; skin-conditioning agent - miscellaneous

Fucus Vesiculosus Fucus Vesiculosus is the alga, Fucus vesiculosus. Skin-conditioning agent - miscellaneous

Fucus Vesiculosus Extract 283-633-7

Fucus Vesiculosus Extract is the extract of the alga, Fucus vesiculosus. Fragrance ingredient; skin-conditioning agent - miscellaneous

Fucus Vesiculosus Powder Fucus Vesiculosus Powder is the powder obtained from dried, ground Fucus vesiculosus.


Halidrys Siliquosa Extract Halidrys Siliquosa Extract is the extract of the alga, Halidrys siliquosa. Skin-conditioning agent - miscellaneous

Halopteris Scoparia Extract Halopteris Scoparia Extract is the extract of the alga, Halopteris scoparia. Skin-conditioning agent - miscellaneous

Sphacelaria Scoparia Extract Sphacelaria Scoparia Extract is the extract of the alga, Sphacelaria scoparia. The accepted scientific name for Sphacelaria scoparia is Halopteris scoparia.

Corn/callus/wart remover

Himanthalia Elongata Extract Himanthalia Elongata Extract is the extract of the thallus of the alga, Himanthalia elongata.



https://online.personalcarecouncil.org/jsp/IngredientDetail.jsp?monoid=29944

Table 2. Current and retired INCI names, definitions, and functions of the brown algae-derived ingredients in this safety assessment1 Ingredient Definition Function Himanthalia Elongata Powder Himanthalia Elongata Powder is the powder obtained from the dried, ground

alga, Himanthalia elongata. Absorbent; binder; viscosity increasing agent -aqueous

Hizikia Fusiforme Extract See Sargassum Fusiforme Extract Hizikia Fusiformis Water Hizikia Fusiformis Water is the aqueous solution of the steam distillates

obtained from the alga, Hizikia fusiformis. The accepted scientific name for Hizikia fusiformis is Sargassum fusiforme. .

Skin protectant

Hizikia Fusiformis Callus Culture Extract Hizikia Fusiformis Callus Culture Extract is the extract of a culture of the callus of Hizikia fusiformis. The accepted scientific name for Hizikia fusiformis is Sargassum fusiforme.

Antifungal agent; antioxidant; hair conditioning agent; skin-conditioning agent - miscellaneous

Hydrolyzed Ecklonia Cava Extract Hydrolyzed Ecklonia Cava Extract is the hydrolysate of an extract of the alga, Ecklonia cava derived by acid, enzyme or other method of hydrolysis.


Hydrolyzed Fucus Vesiculosus Extract 84696-13-9

Fucus Vesiculosus Extract is the extract of the alga, Fucus vesiculosus. Fragrance ingredient; skin-conditioning agent – miscellaneous

Hydrolyzed Fucus Vesiculosus Protein Hydrolyzed Fucus Vesiculosus Extract is the extract of the hydrolysate of Fucus vesiculosus derived by acid, enzyme or other method of hydrolysis.

None reported

Laminaria Cloustoni Extract See Laminaria Hyperborea Extract. Laminaria Diabolica Extract See Saccharina Japonica Extract. Laminaria Digitata Extract 90046-12-1 92128-82-0

Laminaria Digitata Extract is the extract of the alga, Laminaria digitata. Fragrance ingredient; skin protectant; skin-conditioning agent - miscellaneous

Laminaria Digitata Powder Laminaria Digitata Powder is the powder obtained from the dried, ground thallus of the alga, Laminaria digitata.


Laminaria Hyperborea Extract 90046-13-2 92128-82-0

Laminaria Hyperborea Extract is the extract of the alga, Laminaria hyperborea.

Fragrance ingredient; skin protectant

Laminaria Cloustoni Extract 90046-11-0 92128-82-0

Laminaria Cloustoni Extract is the extract of the alga, Laminaria cloustoni. The accepted scientific name for Laminaria cloustoni is Laminaria hyperborea.

Fragrance ingredient

Laminaria Japonica Extract See Saccharina Japonica Extract. Laminaria Japonica Powder Laminaria Japonica Powder is the powder obtained from the dried, ground

alga, Laminaria japonica. The accepted scientific name for Laminaria japonica is Saccharina japonica.


Laminaria Longissima Extract Laminaria Longissima Extract is the extract of the alga, Laminaria longissima. The accepted scientific name for Laminaria longissima is Saccharina longissima


Laminaria Ochroleuca Extract See Saccharina Japonica Extract. Laminaria Saccharina Extract 90046-14-3 92128-82-0

Laminaria Saccharina Extract is the extract of the thallus of the alga, Laminaria saccharina. The accepted scientific name for Laminaria saccharina is Saccharina latissima.

Fragrance ingredient; skin-conditioning agent - miscellaneous

Lessonia Nigrescens Extract Lessonia Nigrescens Extract is the extract of the alga, Lessonia nigrescens. Skin protectant Lessonia Nigrescens Powder Lessonia Nigrescens Powder is the powder obtained from the dried, ground

alga, Lessonia nigrescens. Binder

Macrocystis Pyrifera (Kelp) Macrocystis Pyrifera (Kelp) is the alga, Macrocystis pyriferae. Viscosity increasing agent - aqueous Macrocystis Pyrifera (Kelp) Blade/Pneumatocyst/Stipe Juice Extract

Macrocystis Pyrifera (Kelp) Blade/Pneumatocyst/Stipe Juice Extract is the extract of the juice derived from the blade, pneumatocyst and stipe of the alga, Macrocystis pyrifera.


Macrocystis Pyrifera (Kelp) Extract 347174-92-9

Macrocystis Pyrifera (Kelp) Extract is the extract of the alga, Macrocystis pyrifera.


Macrocystis Pyrifera (Kelp) Juice Macrocystis Pyrifera (Kelp) Juice is the juice expressed from the alga, Macrocystis pyrifera.


Macrocystis Pyrifera (Kelp) Protein Macrocystis Pyrifera (Kelp) Protein is the protein derived from the alga, Macrocystis pyrifera.


Nereocystis Luetkeana Extract Nereocystis Luetkeana Extract is the extract of the alga, Nereocystis luetkeana.

Hair conditioning agent; skin-conditioning agent - miscellaneous

Pelvetia Canaliculata Extract 223751-75-5

Pelvetia Canaliculata Extract is the extract of the alga, Pelvetia canaliculata. Skin protectant; skin-conditioning agent - miscellaneous

Pelvetia Siliquosa Extract Pelvetia Siliquosa Extract is the extract of the alga, Pelvetia siliquosa. Antioxidant; skin protectant; skin-conditioning agent - humectant

Phyllacantha Fibrosa Extract See Cystoseira Baccata Extract.


Table 2. Current and retired INCI names, definitions, and functions of the brown algae-derived ingredients in this safety assessment1 Ingredient Definition Function Saccharina Angustata Extract Saccharina Angustata Extract is the extract of the alga, Saccharina

angustata. Skin-conditioning agent - emollient; skin-conditioning agent - miscellaneous

Laminaria Angustata Extract (Retired) Laminaria Angustata Extract (Retired) is the extract of the alga, Laminaria angustata. The INCI Name, Laminaria Angustata Extract, originally published in 2003, was designated with a retired status in 2015. For an interim period of time, trade name assignments formerly published with the INCI Name Laminaria Angustata Extract will be retained in the retired monograph, and also published with the new name assignment based on the current genus and species name, Saccharina Angustata Extract.


Saccharina Japonica Extract Saccharina Japonica Extract is the extract of the alga, Saccharina japonica. Skin-conditioning agent - miscellaneous

Laminaria Ochotensis Extract (Retired) Laminaria Ochotensis Extract (Retired) is the extract of the alga, Laminaria ochotensis. The INCI Name, Laminaria Ochotensis Extract, originally published in 2008, was designated with a retired status in 2015. For an interim period of time, trade name assignments formerly published with the INCI Name Laminaria Ochotensis Extract will be retained in the retired monograph, and also published with the new name assignment based on the current genus and species name, Saccharina Japonica Extract.

Skin-conditioning agent - emollient

Laminaria Diabolica Extract Laminaria Diabolica Extract is the extract of the alga, Laminaria diabolica. The accepted scientific name for Laminaria diabolica is Saccharina japonica.


Laminaria Japonica Extract 92128-82-0

Laminaria Japonica Extract is the extract of the alga, Laminaria japonica. The accepted scientific name for Laminaria japonica is Saccharina japonica.

Fragrance ingredient

Laminaria Ochroleuca Extract 92128-82-0

Laminaria Ochroleuca Extract is the extract of the alga, Laminaria ochroleuca. The accepted scientific name for Laminaria ochroleuca is Saccharina japonica.

Fragrance ingredient; skin-conditioning agent - miscellaneous

Saccharina Longicruris Extract Saccharina Longicruris Extract is the extract of the alga, Saccharina longicruris.


Sargassum Filipendula Extract Sargassum Filipendula Extract is the extract of the brown alga, Sargassum filipendula.


Sargassum Fulvellum Extract Sargassum Fulvellum Extract is the extract of the alga, Sargassum fulvellum. Skin-conditioning agent - miscellaneous

Sargassum Fusiforme Extract Sargassum Fusiforme Extract is the extract of the brown alga, Sargassum fusiforme.


Hizikia Fusiforme Extract Hizikia Fusiforme Extract is the extract of the alga, Hizikia fusiforme. The accepted scientific name for Hizikia fusiforme is Sargassum fusiforme.

Skin protectant; skin-conditioning agent - miscellaneous

Sargassum Glaucescens Extract Sargassum Glaucescens Extract is the extract of the alga, Sargassum glaucescens.

Antioxidant

Sargassum Horneri Extract Sargassum Horneri Extract is the extract of the alga, Sargassum horneri. Skin-conditioning agent - miscellaneous

Sargassum Muticum Extract Sargassum Muticum Extract is the extract of the alga Sargassum muticum. Skin-conditioning agent - miscellaneous

Sargassum Pallidum Extract Sargassum Pallidum Extract is the extract of the alga, Sargassum pallidum. Antifungal agent; antioxidant Sargassum Siliquastrum Extract Sargassum Siliquastrum Extract is the extract of the alga, Sargassum

siliquastrum. Skin-conditioning agent - miscellaneous

Sargassum Thunbergii Extract

Sargassum Thunbergii Extract is the extract of the alga, Sargassum thunbergii.

Antimicrobial agent

Sargassum Vulgare Extract Sargassum Vulgare Extract is the extract of the alga, Sargassum vulgare. Skin-conditioning agent - miscellaneous

Sphacelaria Scoparia Extract See Halopteris Scoparia Extract. Undaria Peterseniana Extract Undaria Peterseniana Extract is the extract of the alga Undaria peterseniana. Skin-conditioning agent -

miscellaneous Undaria Pinnatifida Extract Undaria Pinnatifida Extract is the extract of the alga, Undaria pinnatifida. Skin protectant; skin-conditioning

agent - miscellaneous Undaria Pinnatifida Cell Culture Extract Undaria Pinnatifida Cell Culture Extract is the extract of a cell culture

suspension of Undaria pinnatifida. Hair conditioning agent; skin-conditioning agent - miscellaneous

Undaria Pinnatifida Leaf/Stem Extract Undaria Pinnatifida Leaf/Stem Extract is the extract of the leaves and stems of Undaria pinnatifida.

Skin-conditioning agent – emollient

Undaria Pinnatifida Powder Undaria Pinnatifida Powder is the powder obtained from the dried, ground alga, Undaria pinnatifida.

Absorbent; binder; viscosity increasing agent - nonaqueous

Undaria Pinnatifida Root Powder Undaria Pinnatifida Root Powder is the powder obtained from the dried, ground root-like structures of the alga, Undaria pinnatifida.

Humectant; skin-conditioning agent - humectant




Table 3. Descriptions of major algae groups Common Name Kingdom Class Description Reference Brown Algae Chromista Phaeophyceae -mostly large, leathery seaweeds

-cellulose wall with alginic acid and fucoidan -derived alginic acid is used as a suspending, emulsifying, gel-forming and film-forming agent

12

Green Algae Plantae Chlorophyta -usually green in color -cellulose cell walls -store starch -beta carotene -chlorophyll a & b

12

Diatoms Stramenopila Bacillariophyceae -golden brown in color -silica cell walls -store oil as food reserve -carotenoids -chlorophyll a & c

12

Chrysophytes Stramenopila Chrysophyta -consists of diatoms, golden-brown algae and yellow-green algae -cellulose cell walls with large amounts of silica -chlorophyll a &c

12,150

Blue Green Algae Monera Cyanophyta -phycobilins present -store glycogen -prokaryotic -chlorophyll a -some are toxic

12

Red Algae Plantae Rhodophyta -phycobilins present -store floridean starch -cellulose cell wall -chlorophyll a & d -source of agar -used as a stabilizer and thickener in many products

12

Dinoflagellates Alveolata Pyrrhophyta -some produce toxins -mostly marine

12,151

Euglenoids Euglenozoa Euglenophyta -common in freshwater -can be parasitic

12,152

Table 4. Taxonomy of brown-algae derived ingredients based on currently accepted scientific name153 Subclass Order Family Genus Ingredient Dictyotophycidae Dictyotales Dictyotacaea Dictyopteris Dictyopteris Polypodioides Extract Dictyotophycidae Dictyotales Dictyotacaea Dictyota Dictyota Coriacea Extract Dictyotophycidae Sphacelariales Sphacelariaceae Sphacelaria Sphacelaria Scoparia Extract Dictyotophycidae Sphacelariales Sphacelariaceae Sphacelaria Halopteris Scoparia Extract Fucophycidae Ectocarpales Chordariaceae Cladosiphon Cladosiphon Novae-Caledoniae Extract Fucophycidae Ectocarpales Chordariaceae Cladosiphon Cladosiphon Okamuranus Extract Fucophycidae Fucales Durvillaeaceae Durvillaea Durvillaea Antarctica Extract Fucophycidae Fucales Fucaceae Ascophyllum Ascophyllum Nodosum Fucophycidae Fucales Fucaceae Ascophyllum Ascophyllum Nodosum Extract Fucophycidae Fucales Fucaceae Ascophyllum Ascophyllum Nodosum Powder Fucophycidae Fucales Fucaceae Fucus Fucus Serratus Extract Fucophycidae Fucales Fucaceae Fucus Fucus Spiralis Extract Fucophycidae Fucales Fucaceae Fucus Fucus Vesiculosus Fucophycidae Fucales Fucaceae Fucus Fucus Vesiculosus Extract Fucophycidae Fucales Fucaceae Fucus Fucus Vesiculosus Powder Fucophycidae Fucales Fucaceae Fucus Hydrolyzed Fucus Vesiculosus Extract Fucophycidae Fucales Fucaceae Fucus Hydrolyzed Fucus Vesiculosus Protein Fucophycidae Fucales Fucaceae Pelvitia Pelvetia Canaliculata Extract Fucophycidae Fucales Fucaceae Pelvitia Pelvetia Siliquosa Extract Fucophycidae Fucales Himanthaliaceae Himanthalia Himanthalia Elongata Extract Fucophycidae Fucales Himanthaliaceae Himanthalia Himanthalia Elongata Powder Fucophycidae Fucales Sargassaceae Cystoseira Cystoseira Amentacea/Caespitosa/

Branchycarpa Extract Fucophycidae Fucales Sargassaceae Cystoseira Cystoseira Baccata Extract Fucophycidae Fucales Sargassaceae Cystoseira Cystoseira Balearica Extract Fucophycidae Fucales Sargassaceae Cystoseira Cystoseira Caespitosa Extract Fucophycidae Fucales Sargassaceae Cystoseira Cystoseira Compressa Extract Fucophycidae Fucales Sargassaceae Cystoseira Cystoseira Compressa Powder Fucophycidae Fucales Sargassaceae Cystoseira Cystoseira Tamariscifolia Extract Fucophycidae Fucales Sargassaceae Halidrys Halidrys Siliquosa Extract Fucophycidae Fucales Sargassaceae Hizikia Hizikia Fusiforme Extract


Table 4. Taxonomy of brown-algae derived ingredients based on currently accepted scientific name153 Subclass Order Family Genus Ingredient Fucophycidae Fucales Sargassaceae Sargassum Hizikia Fusiformis Water Fucophycidae Fucales Sargassaceae Hizikia Hizikia Fusiformis Callus Culture Extract Fucophycidae Fucales Sargassaceae Cystoseira Phyllacantha Fibrosa Extract Fucophycidae Fucales Sargassaceae Sargassum Sargassum Filipendula Extract Fucophycidae Fucales Sargassaceae Sargassum Sargassum Fulvellum Extract Fucophycidae Fucales Sargassaceae Sargassum Sargassum Fusiforme Extract Fucophycidae Fucales Sargassaceae Sargassum Sargassum Glaucescens Extract Fucophycidae Fucales Sargassaceae Sargassum Sargassum Horneri Extract Fucophycidae Fucales Sargassaceae Sargassum Sargassum Muticum Extract Fucophycidae Fucales Sargassaceae Sargassum Sargassum Pallidum Extract Fucophycidae Fucales Sargassaceae Sargassum Sargassum Siliquastrum Extract Fucophycidae Fucales Sargassaceae Sargassum Sargassum Thunbergii Extract Fucophycidae Fucales Sargassaceae Sargassum Sargassum Vulgare Extract Fucophycidae Laminariales Agaraceae Agarum Agarum Cribrosum Extract Fucophycidae Laminariales Agaraceae Alaria Alaria Esculenta Extract Fucophycidae Laminariales Alariaceae Undaria Undaria Peterseniana Extract Fucophycidae Laminariales Alariaceae Undaria Undaria Pinnatifida Extract Fucophycidae Laminariales Alariaceae Undaria Undaria Pinnatifida Cell Culture Extract Fucophycidae Laminariales Alariaceae Undaria Undaria Pinnatifida Leaf/Stem Extract Fucophycidae Laminariales Alariaceae Undaria Undaria Pinnatifida Powder Fucophycidae Laminariales Alariaceae Undaria Undaria Pinnatifida Root Powder Fucophycidae Laminariales Laminariaceae Laminaria Laminaria Cloustoni Extract Fucophycidae Laminariales Laminariaceae Saccharina Laminaria Diabolica Extract Fucophycidae Laminariales Laminariaceae Laminaria Laminaria Digitata Extract Fucophycidae Laminariales Laminariaceae Laminaria Laminaria Digitata Powder Fucophycidae Laminariales Laminariaceae Laminaria Laminaria Hyperborea Extract Fucophycidae Laminariales Laminariaceae Saccharina Laminaria Japonica Extract Fucophycidae Laminariales Laminariaceae Saccharina Laminaria Japonica Powder Fucophycidae Laminariales Laminariaceae Laminaria Laminaria Longissima Extract Fucophycidae Laminariales Laminariaceae Saccharina Laminaria Ochroleuca Extract Fucophycidae Laminariales Laminariaceae Laminaria Laminaria Saccharina Extract Fucophycidae Laminariales Laminariaceae Macrocystis Macrocystis Pyrifera (Kelp) Fucophycidae Laminariales Laminariaceae Macrocystis Macrocystis Pyrifera (Kelp)

Blade/Pneumatocyst/Stipe Juice Extract Fucophycidae Laminariales Laminariaceae Macrocystis Macrocystis Pyrifera (Kelp) Extract Fucophycidae Laminariales Laminariaceae Macrocystis Macrocystis Pyrifera (Kelp) Juice Fucophycidae Laminariales Laminariaceae Macrocystis Macrocystis Pyrifera (Kelp) Protein Fucophycidae Laminariales Laminariaceae Nereocystis Nereocystis Luetkeana Extract Fucophycidae Laminariales Laminariaceae Saccharina Saccharina Angustata Extract Fucophycidae Laminariales Laminariaceae Saccharina Saccharina Japonica Extract Fucophycidae Laminariales Laminariaceae Saccharina Saccharina Longicruris Extract Fucophycidae Laminariales Lessoniaceae Ecklonia Ecklonia Cava Extract Fucophycidae Laminariales Lessoniaceae Ecklonia Ecklonia Cava Water Fucophycidae Laminariales Lessoniaceae Ecklonia Ecklonia Kurome Extract Fucophycidae Laminariales Lessoniaceae Ecklonia Ecklonia Kurome Powder Fucophycidae Laminariales Lessoniaceae Ecklonia Ecklonia/Laminaria Extract Fucophycidae Laminariales Lessoniaceae Ecklonia Ecklonia Maxima Extract Fucophycidae Laminariales Lessoniaceae Ecklonia Ecklonia Maxima Powder Fucophycidae Laminariales Lessoniaceae Ecklonia Ecklonia Radiata Extract Fucophycidae Laminariales Lessoniaceae Ecklonia Hydrolyzed Ecklonia Cava Extract Fucophycidae Laminariales Lessoniaceae Eisenia Eisenia Arborea Extract Fucophycidae Laminariales Lessoniaceae Lessonia Lessonia Nigrescens Extract Fucophycidae Laminariales Lessoniaceae Lessonia Lessonia Nigrescens Powder


Table 5. General characteristics and geographic distribution of brown algae species Species (common name) Description Distribution/Habitat/Ecology References Agarum cribrosum - North Atlantic (Massachusetts to east Greenland) and

North Pacific (Washington state to Japan and Russia) Forms thick beds at depths of 10-12 m

153

Alaria esculenta (dabberlocks, badderlocks, winged kelp)

Olive or yellow-brown fronds to 4 m long and 25 cm wide, more often about 1 m and 7.5 cm wide. Attached by a root-like holdfast at the base from which a narrow flexible stipe arises which continues into the leafy part of thealgae as a distinct mid-rib, generally with a yellow-brown color. The reproductive structures, apparent as dark-brown areas, are confined to unbranched leafy appendages borne on the stipe, usually in two rows.

North Atlantic Ocean Generally growing on rock in wave-exposed places, often forming a band at low water and in the shallow subtidal, but also occurring in tidal pools in the lower shore.

153,154

Ascophyllum nodosum (asco, sea whistle, bladderwrack, rockweed)

Closely related to Fucus. Up to 3 m in height and is yellow in areas exposed to sunlight and dark green or brown in its shaded parts. Single bladders are central in long, strap-like fronds. Fronds hang downwards. Multiple fronds grow from each basal holdfast; generally regenerates new fronds from base when one of the larger fronds is damaged. Reproduction takes place in spring in yellow receptacles, which develop in response to short days in autumn, mature during winter, and are at their most prolific in spring. Eggs and sperm are released into water, and eggs release a low molecular weight pheromone, finnavarene.

North Atlantic basin (Virginia to Spain) Has been observed in San Francisco Bay, but does not persist there. Sheltered intertidal rocks in shallow (usually where it is exposed at low or extreme low tides)

153-156

Cystoseira baccata (bushy berry wrack) also known as Phyllacantha fibrosa

Thallus to 1 m long, usually solitary, attached by a thick, conical attachment disc. Axis simple or branched, and flattened; apex smooth and surrounded during periods of active growth by incurved young laterals. Lateral branch systems alternate, radially symmetrical, profusely branched in a repeatedly pinnate fashion and bearing sparse, filiform, occasionally bifurcated appendages on the branches; deciduous, leaving decurrent bases which give an irregular, zigzag outline to the axis. Air vesicles present in axes of branches of higher order, sometimes in chains; seasonal, particularly numerous in autumn. Receptacles 1-5 cm long, formed from axes of ultimate ramuli, irregularly nodose and bearing simple, filiform appendages.

S England, W Ireland north to W Scotland. Has been noted down to Morocco and in Mediterranean Sea. Lower intertidal in large sandy pools or lagoons, mostly in persistent stands.

153,154

Cystoseira tamariscifolia (bushy rainbow wrack)

Solitary thalli, up to 1 m long, bushy, with a pronounced greenish or bluish iridescence when submerged or wet; attached by a conical disc. Axis is cylindrical, up to 60 cm long, usually branched and with an inconspicuous apex. Lateral branch systems arising in spiral sequence, up to 60 cm long, profusely branched in a repeatedly pinnate fashion, showing radial symmetry with simple or bifid spine-like appendages: deciduous, leaving prominent scars or stumps. Cryptostomata present on branches and appendages. Ovoid air vesicles often present in axes of ultimate ramuli. Receptacles 1-2 cm long, formed from terminal regions of ultimate ramuli.

Western Mediterranean Sea/northern Africa to Ireland Large intertidal rock pools and lagoons and shallow subtidal shores

153,154

Dictyopteris polypodioides [Dictyopteris membranacea (Retired)]

Thallus flat and leaf-like, to 300 mm long and 20 - 30 mm broad; fronds olive to yellow-brown, translucent, and somewhat regularly dichotomously forked with a prominent midrib extending to the apices. Margins sometimes split to midrib. Has an unpleasant smell shortly after collection, which degenerates quickly.

Ireland (except for east coast), west Scotland, Wales, southwest England, to Portugal and West Africa Large pools at low water and shallow subtidal shores

153,154

Fucus serratus (serrated wrack, saw wrack, toothed wrack)

Dichotomously branched fronds arising from a small disc via a short stipe; distinct midrib.Algae grows to 300 mm with terminal, compressed receptacles with warty conceptacles. It is easily recognized by its saw-toothed frond, and a lack of swollen receptacles.

Widely distributed on all coasts of Britain and Ireland. Baltic Sea to Spain and Canary Islands. Introduced to Nova Scotia and has spread to New Brunswick and Maine. Zone forming on sheltered and semi-exposed shores.

153-155

Fucus spiralis (jelly bags, spiral wrack, flat wrack spiraled wrack)

Fronds lack bladders; elongated air bladders are on either side of the midrib. Fronds have twisted, dichotomous branches. This species is up to 20 cm long, attached to the substratum with a discoid holdfast. Color ranges from dark brown to olive-green.

North Atlantic and North Pacific; Baltic Sea to Morocco/Canary Islands and New York; Alaska to California. Introduced to Mediterranean Sea (France). Uppermost species of Fucus that occurs on shore.

155


Table 5. General characteristics and geographic distribution of brown algae species Species (common name) Description Distribution/Habitat/Ecology References Fucus vesiculosus (paddy tang, red fucus, dyers fucus, swine tang, sea ware, bladder, rockweed, bladderwrack, popping wrack, wrack)

Paired bladders occur on either side of a prominent midrib. Frond is generally not strongly spiraled and receptacles do not have a sterile rim, and frond does not have a serrated margin. Attached by a small, strong disc which gives rise to a short stipe. This species is 15 to 90 cm long and 0.6 to 2.5 cm wide. Reproductive receptacles are swollen areas at tips of fronds that have many flask-shaped cavities called conceptacles, which house male and female reproductive structures known as antheridia (borne on antheridiophores) and oogonia (containing 8 eggs), respectively. Eggs and sperm are liberated onto surface of receptacles and a pheromone (sex-attracting substance) is released by eggs that attract sperm. Fertilization results in a zygote that forms a new Fucus adult.

North Atlantic (Canadian Arctic, Russia, White Sea, Baltic Sea) south to Canary Islands and West Indies Midshore zone A bladderless form occurs on more wave-exposed shores in the NE Atlantic. Grows in various conditions, from saline lagoons to exposed rocky shores, as well as on sheltered rocky shores. Forms dense canopies.

153-155,157

Halidrys siliquosa (podweed, sea oak) Thallus 30 - 130 cm long, tawny to yellow-brown ochre, tough and leathery; attached by a large, discoid holdfast, giving rise to compressed, irregularly alternately branched fronds, with several orders of close branching in the same plane. Pod-shaped, segmented air bladders are produced replacing some lateral branches. Reproductive conceptacles forming in swollen conceptacles at apices of branches

Northeast Atlantic (Norway/Baltic Sea to Morocco) Large, mid-intertidal pools, often dominating in very large, sunny pools, but more often forming occasional stands. Occasionally forming extensive forests in shallow subtidal to about 10 m, generally in current-exposed locations. Widespread and common. Halidrys produces meroditerpenoids that seemingly act as antifouling agents preventing other organisms adhering to surface of the algae.

153,154

Halopteris scoparia (sea flax weed) also known as Sphacelaris scoparia

Stypocaulon scoparium may be synonymous

Northwest Atlantic (Baltic Sea to Canary Islands) and Mediterranean Sea

153

Himanthalia elongata (thongweed, buttonweed, sea spaghetti, sea thong, sea haricots)

Long thong-like fronds, basal mushroom-like buttons. Thallus consisting of a button-shaped vegetative thallus to 30 mm wide and 25 mm high, and a long, narrow, strap-like, sparingly branched, light yellow-brown reproductive receptacle to 2 m in length and up to 10 mm in width, on which conceptacles are borne. Buttons, initially club-shaped but later mushroom-like, develop from zygotes in late summer, mature in winter, and begin to form reproductive receptacles in January/February. Some 4-6 dichotomies are produced at this stage, and fronds then elongate and thicken, developing no further branches, and become reproductively mature in July-September.

Northwest Atlantic Ocean (Scandinavia to Spain) Gently sloping rocks, particularly on semi-wave-exposed shore, on which they may form a distinct zone at low water. Sparse populations sometimes develop in sheltered lagoons where thealgae are more yellow and less flattened.

153,154

Laminaria cloustoni [Laminaria hyperborea] (kelp, may weed, kelpie, liver weed, mirkle, pennant weed, strapwrack, cuvie, tangle, split whip wrack, sea rods, forest kelp, northern kelp)

Dark brown, to 2 m in length; with a claw-like, conical holdfast, a rough, rigid stipe which generally rises up out of the water, and is covered in epiphytes when older, and a laminate blade to 1.5 m long dividing into finger-like segments. Stipe is rugose (rough) when older, circular in cross-section, and snaps easily when bent; the holdfast is conical.

Northwest Atlantic Ocean (Scandinavia to Spain) Common at extreme low water in wave-exposed areas, and in the subtidal in optically clear water growing on rock to a depth of 32 m. Forms extensive closed communities at depths of 0 - 24 m. There are usually large quantities of ephytic red algae growing on the older stipes; the old fronds are cast off in spring and new ones grow below for a time.

153,154

Laminaria digitata (kelp) Dark brown, to 2 m in length; with a claw-like holdfast, a smooth, flexible stipe, and a laminate blade to 1.5 m long split into finger-like segments. The stipe is oval in cross-section, and does not snap easily when bent. Underwater algae are more golden in color in sunlight.

North Atlantic (Arctic Canada/ Baltic Sea/Russia to Spain and New England) Very common in lower intertidal and shallow subtidal growing on rock. May form extensive meadows at low tide.

153,154

Laminaria hyperborea (kelpie, liver weed, mirkle, pennant weed, strapwrack, cuvie, tangle, split whip wrack)

Dark brown, to 2 m in length; with a claw-like, conical holdfast, a rough, rigid stipe which generally sticks up out of the water, and is covered in epiphytes when older, and a laminate blade to 1.5 m long dividing into finger-like segments. Stipe is rugose (rough) when older, circular in cross-section, and snaps easily when bent; the holdfast is conical.

Northeast Atlantic (Scandinavia/Iceland to Spain and Canary Islands) Common at extreme low water in wave-exposed areas, and in subtidal in optically clear water growing on rock to a depth of 32 m. Forms extensive closed communities at depths of 0-24 m; there are usually large quantities of ephytic red algae growing on the older stipes; the old fronds are cast off in spring and new ones grow below for a time.

153,154,158


Table 5. General characteristics and geographic distribution of brown algae species Species (common name) Description Distribution/Habitat/Ecology References Laminaria saccharina [The accepted scientific name is Saccharina latissima] (sea belt, poor man's weather glass, sweet wrack, sugar wrack, sugar tang, oarweed, tangle, kelp, sugar sea belt, sweet tangle, sugarwrack, zuckertang)

Yellow brown, to 3 m in length; with a claw-like holdfast, a small, smooth, flexible stipe, and an undivided laminate blade to 3 m long with parallel, ruffled sides and an elongated, tongue-like appearance. Frond is characteristically dimpled with regular bullations (depressions). Stipe is relatively small, cylindrical in section and more flexible than those of Laminaria digitata and Laminaria hyperborea. It is only species in the NE Atlantic Ocean with an undivided frond, distinct bullations, and a frilly margin.

Circumboreal (Atlantic Ocean: Canada, Scandinavia, Greenland, Iceland to Galicia, Spain and Maine, but not known in the Bay of Biscay; Pacific Ocean: Alaska to California, Japan, Korea, Central Polynesia, India, New Zealand) Intertidal pools and occasional in shallow subtidal areas, becoming more abundant at low water in sheltered localities with fast-moving water, such as rapids systems. In subtidal, it is characteristic of intermittently disturbed areas.

153,154

Macrocystis pyrifera (giant kelp, sea ivy, giant pacific kelp)

This species reaches 45 meters long and grow in waters 6 - 20 (possibly up to 80) m deep, and grow at up to 30 cm per day. Now believed to be a monospecific genera ranging from intertidal to deep water with environments dictating morphology.

Eastern and southern Pacific Ocean in both hemispheres (Alaska to New Zealand and Australia) Dominant canopy-forming algae in southern and central California.

153,159,160

Pelvetia canaliculata (channeled wrack, cow tang)

This species is 80-120 mm long, yellow-brown in color, turning black when dry, and often so dry that fronds disintegrate when trodden upon; regularly dichotomously branched with a distinct channel on underside (side nearest rock), which holds moisture and apparently helps algae survive at very high levels on shore. Reproduction in conceptacles visible as dots on warty terminal receptacles. Usually infected by a fungus which may assist in allowing it to survive high in intertidal zone.

NE Atlantic from the Faroe Islands to Portugal Occurring very high on shore, generally above mean high water neap tides, on wave-exposed and sheltered shores, but absent from very exposed rocky shores.

153-155

Sargassum muticum Thallus bushy, elongated, yellowish-tawny to dark brown, generally to 4 m long; tough, cylindrical, repeatedly alternately pinnately branched to the third or fourth order; whorls of distinctly flattened sculpted leaves at the base (resembling the leaves of Holly); with characteristic rounded-elliptical air bladders above and below, formed terminally. Reproductive receptacles below, formed in the axils of spiny leaves; spectacularly fecund. Basal holdfast penetrating and conical, persisting for several years. Reproductive plants detach easily, and continue to reproduce while drifting, and spreading the reproductive zygotes that develop on the surfaces of the receptacles. Terminal air bladders below; receptacles in the axils of spiny leaves.

Native to Japan; spread to China and Korea. Invasive in France, Spain and Portugal; western Mediterranean; Alaska south to Mexico. Throughout the intertidal in pools, but largest and commonest at low water.

153,154

Undaria pinnatifida (sea mustard, precious sea grass, wakame)

Thallus laminate, yellowish to dark brown, usually 1 - 2 m, occasionally 3 m or more in length; holdfast spreading, dichotomously branched and claw-like, giving rise to a flattened oar-like stipe with a "fried-egg" like margin with small proliferations and basally with beautifully lobed sporophylls that coil around it when mature; stipe continuing into the fond as a flattened midrib that bears broadly lobed laciniate fronds with a roughly pyramidal shape. Frilly sporophylls coiling around the base of the flattened stipe at the base. A similar flattened midrib is not found in any other kelp in the Atlantic. Alaria esculenta has a midrib which is not flattened and the frond of Alaria is not lobed, although it may be similarly laciniate.

Native to Pacific Russia, Japan, China and Korea. NE Ireland, S England, NW France, NW Spain, Mediterranean Lower intertidal and very shallow subtidal (no more than a few m), particularly in sheltered locations, growing particularly on marinas, buoys, and similar floating structures in harbors. Often occurring on boat-hulls.

153


http://www.seaweed.ie/descriptions/Laminaria_digitata.php

http://www.seaweed.ie/descriptions/Laminaria_hyperborea.php

Table 6. Chemical and physical properties of some brown algae-derived ingredients

Property Value Reference

Ascophyllum Nodosum Extract Physical Form Liquid

Viscous liquid Solid flakes

161,162 163 6

Color Black Dark brown

Dark brown (aq. ext)

6,161 162 163

Odor Marine-like/Fish-like Characteristic, seaweed (aq. ext)

Odorless

161,162 163 6

Density/Specific Gravity 1.17 1.1 (aq. ext.)

161 163

Bulk Density (g/mL) 0.58 6 Viscosity kg/(s m) < 0.1 161 Melting Point oC 0 (aq. ext.)

> 300 163 6

Boiling Point oC 100 100 (aq. ext.)

65 – 96

161 163 162

Water Solubility g/L @ 20 oC & pH 7.4 – 7.5 @ 20 oC

> 10,000 100% 100%

6 161,162

163 Other Solubility g/L Acetone @ 22 oC Ethyl acetate @ 22oC Methanol @ 22 oC

0.007 0.009 0.251

6 6 6

log Pow -3.3 est. 5,6 Particle size > 0.250 mm, 93.5%

< 0.045 mm, none 6

Ascophyllum Nodosum Powder Physical Form Flakes or powder

Powder 164 165

Color Olive green Green

164 165

Odor Marine-like Characteristic, fish-like

164 165

Water Solubility g/L Insoluble 164 Ecklonia Cava Extract

Physical Form Powder (alcohol ext) 9 Color Brown (alcohol ext) 9

Halidrys Siliquosa Extract (aq.) Physical Form Liquid 65 pH 5 65 Density 1.02 65 aq. = aqueous; ext. = extract


Table 7. Methods of manufacture for brown algae-derived ingredients Ingredient (characterization) Method of Manufacture Reference Alaria Esculenta Extract trade name mixture consisting of Alaria Esculenta Extract in butylene glycol and water: harvesting/identification washing grinding

extraction with the solvents and butylene glycol and water filtration quality control packaging quality control 19

Alaria Esculenta Extract trade name mixture consisting of Alaria Esculenta Extract in butylene glycol and water – dried before extraction: harvesting/identification washing drying grinding extraction with the solvents butylene glycol and water filtration quality control packaging quality control

19

Alaria Esculenta Extract trade name mixture containing Alaria Esculenta Extract in Caprylic/Capric Triglycerides: harvesting/identification drying grinding extraction with solvent caprylic/capric triglyceride filtration quality control packaging quality control

20

Ascophyllum Nodosum Extract A trade name mixture containing 4.7% Ascophyllum Nodosum Extract in 94.5% water, reported a manufacturing process consisting of grinding the algae, extraction by water, fucoidan purification and ultrafiltration.

21 Ascophyllum Nodosum Extract The species Ascophyllum nodosum is grinded, extracted by water, then undergoes fucoidan purification and ultrafiltration. 22 Cladosiphon Okamuranus Extract (high in fucoidan)

Cladosiphon okamuranus is hydrolyzed in 0.05 M or 0.5 M hydrochloric acid at 80°C for 30 min and then is neutralized with sodium hydroxide. Salt is removed by electrodialysis and then hydrolysate is lyophilized.

47

Cystoseira Tamariscifolia Extract Cystoseira Tamariscifolia Extract and Caprylic/Capric Triglycerides: extraction with supercritical carbon dioxide

49

Dictyopteris Polypodioides Extract (high fractions of C11 hydrocarbons and sulfur compounds)

Air-dried algae material is extracted with diethyl ether. Solvent is removed vacuum distillation leaving a crude concrete extract. Crude extract is treated with hydrodistillation followed by liquid-liquid extraction with diethyl ether to obtain the essential oil.

23

Dictyopteris Polypodioides Extract (high fraction of sulfur compounds)

Air-dried algae material is extracted with diethyl ether. Solvent is removed by vacuum distillation leaving a crude concrete extract. Crude extract is then subjected to supercritical fluid (CO2) extraction.

23

Dictyopteris Polypodioides Extract (high fractions of sesquiterpenes)

Air-dried algae material is extracted with diethyl ether. Solvent is removed vacuum distillation leaving a crude concrete extract. Crude extract is mixed with water and irradiated in a microwave oven (focused microwave-assisted hydrodistillation).

23

Ecklonia Cava Extract Fresh, semidried Ecklonia cava seaweed is dried and crushed followed by alcohol (i.e., food-grade ethanol) extraction, purification, filtration, and concentration steps.

9

Ecklonia Cava Extract Small pieces of Ecklonia cava fronds (~ 5 cm; 30 kg) are placed in 750 L of distilled water in the presence of enzymes (300 g pectinase and 300 g cellulase). Suspension is stirred for 24 h at 50°C, centrifuged at 3000 g for 20 min at 4°C, and vacuum filtered. Three volumes of 60% ethanol are then added for 18 h of extraction. Solution is filtered and concentrated using a rotary evaporator. Concentrated solution is made into powder using a spray dryer.

92

Ecklonia Cava Extract (high in polyphenols) Dried Ecklonia cava powder is extracted with ethanol, concentrated, and freeze-dried. 24 Fucus Spiralis Extract trade name mixture containing Fucus Spiralis Extract (“1 - 3% dry extract” (further details not provided)) in butylene glycol and water:

harvesting/identification washing grinding extraction with the solvents butylene glycol and water addition of phenyllactic acid filtration quality control packaging quality control

25

Fucus Vesiculosus Extract trade name mixture containing water, alcohol and Fucus Vesiculosus Extract: dried raw material extract with 30% ethanolic solution filtrate concentration filtrate packaging

26

Fucus Vesiculosus Extract trade name mixture containing sodium sulfate and Fucus Vesiculosus Extract: dried raw material extract with 30% ethanolic solution filtrate concentration add anhydrous sodium sulfate packaging

26

Fucus Vesiculosus Extract trade name mixture containing Fucus Vesiculosus Extract in caprylic/capric triglyceride: harvesting/identification washing grinding extraction with the solvent caprylic/capric triglyceride filtration quality control packaging quality control

27

Fucus Vesiculosus Extract (28.8% polyphenols) Ethanol (30% - 35% aq.) extraction of Fucus vesiculosus (10% w/w) is performed at room temperature under mechanical stirring for 4 h. After filtration on a filter press, liquid phase undergoes an initial purification step to remove alginates by precipitation in presence of excess calcium chloride. Liquid phase undergoes a second purification step involving diafiltration to remove iodine and low molecular weight compounds. Extract is freeze-dried to obtain a powder extract.

93

Fucus Vesiculosus Extract (18% polyphenols plus 0.0012% fucoxanthin)

Ethanol (50% - 70% aq.) extraction of Fucus vesiculosus (10% w/w) is performed to solubilize a greater amount of carotenoids at room temperature under mechanical stirring for 2 h. After filtration on a filter press, liquid phase undergoes an initial purification step to remove alginates by precipitating them in presence of excess calcium chloride. After solid-liquid separation, a second extraction is performed under same conditions. Two liquid phases are then blended, submitted to diafiltration to remove iodine and low molecular weight compounds, and freeze-dried to obtain a powder extract.

93

Fucus Vesiculosus Extract Dried algae material is extracted with water for 24 h, with stirring at room temperature. Residue is then removed by filtration to give a slightly brown colored extract.

44

Hizikia Fusiforme Extract trade name mixture containing water butylene glycol and Hizikia Fusiforme Extract: dried raw material extract with 80% ethanolic solution filtrate concentration add 50% 1,3-butylene glycolic solution filtrate packaging

26


Table 7. Methods of manufacture for brown algae-derived ingredients Ingredient (characterization) Method of Manufacture Reference Laminaria Digitata Extract (high in oligosaccharides)

An aqueous extraction is conducted followed by enzymatic depolymerization that breaks the polysaccharide into oligosaccharides (e.g., smaller polymers with 3 to 10 sugar components). Final process involves chelating oligosaccharide with zinc sulfate (0.1% zinc-pyrrolidone).

29

Laminaria Digitata Extract trade name mixture containing Laminaria Digitata Extract in caprylic/capric triglyceride: harvesting/identification washing drying grinding extraction with the solvent caprylic/capric Triglyceride filtration quality control packaging quality control

28

Laminaria Digitata Extract trade name mixture containing Laminaria Digitata Extract in water and propylene glycol: harvesting/identification washing grinding extraction with the solvents water and propylene glycol addition of methylparaben and propylparaben filtration quality control packaging quality control

30

Laminaria Hyperborea Extract trade name mixture containing Laminaria Hyperborea Extract in water: harvesting/identification washing grinding extraction with water addition of benzylic alcohol and dehydroacetic alcohol filtration quality control packaging packaging quality control

31

Laminaria Japonica Extract (low-molecular weight fucoidan)

Enzyme hydrolysis 52

Laminaria Japonica Extract Algae is rinsed with tap water to remove salt and dried in an air dryer at 60∘C for 40 h. Dried material is ground with a hammer mill, and powder stored at −20∘C until used. Dried powder (2.5 kg) is extracted 3 times with 96% (v/v) ethanol for 3 h at 70°C. Combined extracts are filtered and concentrated under reduced pressure to obtain ethanol extracts

46

Laminaria Japonica Extract Freshly collected algae material is air dried with a fan for 24 h then ground into a fine powder. 5 g of powder is added to 100 mL of 1:1 water:propylene glycol at room temperature for 1 day. This procedure is repeated 2 times, and the combined extracts were stored at −20°C until use.

51

Laminaria Japonica Extract, Nereocystis Leutkeana, and Macrocystis Pyrifera

trade name mixture containing Laminaria Japonica, Nereocystis Leutkeana, and Macrocystis Pyrifera Extract: test of acceptance processing (mechanical grinding/milling) extraction with pentaerythrityl tetraethylhexanoate at specific pH and temperature for specific duration filtration batch adjustments (refiltration) sample for QC pack sample for Micro shipping

32

Laminaria Japonica Powder Dried algae is pulverized to desired size. 48 Laminaria Ochroleuca Extract trade name mixture consisting on Laminaria Ochroleuca extract in Caprylic/Capric Triglyceride:

harvesting/identification washing grinding extraction with the solvent caprylic/capric triglyceride filtration quality control packaging quality control

33

Laminaria Saccharina Extract trade name mixture containing Laminaria Saccharina Extract in water and propylene glycol: harvesting/identification washing grinding extraction with solvents: water + propylene glycol mixture (addition of preservatives) filtration quality control

34

Laminaria Saccharina Extract trade name mixture containing Laminaria Saccharina Extract (“1-2.5% dry extract” (no other details provided)) in water and butylene glycol: harvesting/identification washing grinding extraction with the solvents water and butylene glycol mixture addition of preservatives filtration quality control

34

Macrocystis Pyrifera Extract Macrocystis Pyrifera Extract (“1-3% dry extract (no other details provided)) – extracted in water with added methylpropanediol: harvesting washing grinding extraction (water) centrifugation filtration addition of 20% Methylpropanediol filtration

35

Pelvetia Canaliculata Extract trade name mixture containing Pelvetia Canaliculata Extract (“1 - 3% dry extract” (no other details provided)) in butylene glycol and water: harvesting/identification washing drying grinding extraction with the solvents vegetable butylene glycol and water filtration quality control packaging quality control

36

Pelvetia Canaliculata Extract trade name mixture containing Pelvetia Canaliculata Extract (“1 - 3% dry extract” (no other details provided)) in water and propylene glycol: harvesting/identification washing grinding extraction with the solvents water and propylene glycol addition of methylparaben and propylparaben filtration quality control packaging quality control

36

Pelvetia Canaliculata Extract trade name mixture containing Pelvetia Canaliculata Extract (“0.5 - 3% dry extract” (no other details provided)) in water: harvesting/identification washing grinding extraction with water addition of benzylic alcohol and dehydroacetic acid filtration addition of trisodium citrate dehydrate filtration quality control packaging quality control

37

Pelvetia Canaliculata Extract trade name mixture containing Pelvetia Canaliculata Extract in water: harvesting/identification washing grinding extraction with water addition of phenoxyethanol and sorbic acid filtration quality control packaging quality control

38

Pelvetia Canaliculata and Laminaria Digitata Extract

trade name mixture containing Pelvetia Canaliculata and Laminaria Digitata extracted in propylene glycol with panthenol: harvesting/identification washing grinding extraction with the solvent propylene glycol filtration quality control mixture filtration quality control packaging quality control

39


trade name mixture containing Pelvetia Canaliculata and Laminaria Digitata extracted in butylene glycol with preservatives: harvesting/identification washing grinding extraction with butylene glycol filtration quality control mixture filtration quality control packaging quality control

39


trade name mixture containing Pelvetia Canaliculata and Laminaria Digitata extracted in butylene glycol without preservatives: harvesting/identification washing grinding extraction with butylene glycol filtration quality control mixture filtration quality control packaging quality control

40

Sargassum Fusiforme Extract and Undaria Pinnatifida Extract (high in fucosterol and phytol)

Microwave-assisted extraction coupled with high-speed countercurrent chromatography. 41


Table 7. Methods of manufacture for brown algae-derived ingredients Ingredient (characterization) Method of Manufacture Reference Sargassum Fusiforme Extract and Undaria Pinnatifida Extract (high in lipids and antioxidant compounds)

Supercritical fluid extraction and subcritical water extraction. 41

Sargassum Glaucescens Extract trade name mixture containing 20% Sargassum Glaucescens Extract, 79% water and 1% phenoxyethanol: grinding extraction preservative addition sterilization filtration packaging storage

166

Undaria Pinnatifida Extract (high in fucoidan) Algae material is hydrolyzed in 0.05 or 0.5 M hydrochloric acid at 80°C for 30 min then neutralized with 1 M sodium hydroxide. Resulting material is desalted by gel filtration and hydrolysate lyophilized.

66

Undaria Pinnatifida Extract trade name mixture containing Undaria Pinnatifida Extract in water and propylene glycol: harvesting/identification drying grinding extraction with solvents water and propylene glycol, and addition of preservatives (methylparaben and propylparaben) filtration quality control packaging quality control

43

Undaria Pinnatifida Extract trade name mixture containing Undaria Pinnatifida Extract in Caprylic/Capric Triglyceride: harvesting of fertile sporophytes fragment isolation of gametophyte culture in liquid medium gametophyte separation freeze-dried gametophyte - quality control extraction with the solvent caprylic/capric triglyceride filtration quality control packaging quality control

42

Abbreviations: aq. = aqueous; HPLC = high-performance liquid chromatography

Table 8. Constituents in brown algae Constituent(s) Description Alkaloids Tyramine (TYR, 4-hydroxyphenylethylamine) has been detected in Laminaria saccharina.167 The alkaloids found in marine algae may be divided into three groups:

phenylethylamine alkaloids, indole and halogenated indole alkaloids, and other alkaloids. Amino acids Brown algae contain all of the essential amino acids and are greater in threonine, valine, leucine, lysine, glycine, and alanine than are the green and blue algaes.41 Fucus spiralis was

reported to contain 63.5% essential amino acids per total protein, containing leucine (5.5 mg/g protein), isoleucine (15.3 mg/g protein), lysine (12.5 mg/g protein), glutamic acid (12.1 mg/g protein), arginine (11.7 mg/g protein), serine (11.5 mg/g protein), valine (11.1 mg/g protein), and threonine (10.9 mg/g protein).168

Betaines Glycinebetaine, γ-aminobutyric acid betaine, and/or trigonelline have been found in Alaria esculenta, Ecklonia maxima, Ecklonia radiata, Eisenia arborea, Laminaria digitata Macrocystis pyrifera, Nereocystis luetkeana, Saccharina angustata, Saccharina japonica, and Undaria pinnatifida.169

Iodine The concentration of iodine in Alaria esculenta was reported to have a range of approximately 200 mg/kg (dry wt) to approximately 700 mg/kg (dry wt) depending on year, season, location, and whether it was collected in the wild, a monoculture, or an integrated culture.170 Fucus vesiculosus contains between 0.03% and 0.2% iodine in dried material.171 The iodine content is highest in the spring in freshly cut young blades. In Laminaria digitata, iodine content is highest in late autumn and winter (0.75% to 1.20% dry wt) and lowest in summer (0.25% to 0.60% dry wt).172 Iodine content for Fucus spiralis and Laminaria ochroleuca have been reported to be 232.7 and 883.5 mg/kg dry wt.168

Laminarins Laminarins are basically a class of low molecular weight storage β-glucans. These are composed of (1,3)-β-D-glucan and can be up to 35% of the dry weight of brown algae.173 Lipids Fucosterol and fucosterol derivatives are present in brown algae.41 Tocopherols, and sterols are also found in brown algae. Omega-3 fatty acids Omega-3 fatty acids include stearidonic acid and hexadecatetraenoic acid.174 These make up to 40% of the total fatty acid content in Undaria pinnatifida. Phenolic compounds, polyphenols, and phlorotannins

Phlorotannins are found in brown algae.41 Flavonoids are integral structural components of cell walls (e.g., eckol, phlorofucofuroeckol A, dieckol, catechin, and epigallocatechin).

Pheromones The pheromones include lamoxirene 4 (e.g., Agarum cribrosum, Ecklonia radiata, Eisenia arborea, Laminaria digitata, Laminaria hyperborea, Laminaria japonica, Laminaria saccharina, Saccharina angustata, Undaria pinnatifida, Macrocystis pyrifera, and Nereocystis luetkeana), fucoserratene 6 (e.g., Fucus serratus, Fucus spiralis, and Fucus vesiculosus), hormonsirene 8 (e.g., Durvillaea antarctica), and finavarrene 12 (Ascophyllum nodosum). The major constituents of the essential oil of Dictyopteris polypodioides are C11 hydrocarbons sulfur products such as 3-hexyl-4,5-dithiacycloheptanone.23

Phytohormones Auxins (plant hormones that cause the elongation of cells in shoots and are involved in regulating plant growth), such as indoleacetic acid are found in the genera Macrocystis, Laminaria, Fucus, Ascophyllum).41,175 Cytokinins (genera Fucus, Ascophyllum, Sargassum, Macrocystis), gibberellins (genus Fucus), abscisic acid (genera Ascophyllum, Laminaria), and polyamines (genus Dyctiota) are also found.

Pigments Carotenoids including fucoxanthin, β-carotene, zeaxanthin, violaxanthin, and antheraxanthin are found in brown algae.41 These vary with season. Protein The protein content of algae varies according to species and season.14,41 In general, the protein fraction of brown algae is low (1% to 24% dry wt.) compared with that of green or red

algae (4% to 50% dry wt). Except for the species Undaria pinnatifida, which has a protein content between 11% and 24% (dry wt.), most commercial brown algae have a protein content lower than 15% (dry wt; e.g., Ascophyllum nodosum, 3% to 15%; Fucus vesiculosus, Himanthalia elongate, and Laminaria digitata, 8% to 15%). The protein content of Fucus sp. tend to range from 3% to 11% (e.g., Fucus spiralis, 9.71% dry weight).168

Sterols Sterols found in brown algae include desmosterol, ergosterol, fucosterol, cholesterol, campesterol, stigmasterol, and β-sterol.60,61 Terpenoids Terpenes, phenolic compounds, and meroterpenes make up the three major classes of secondary metabolites in brown seaweed.41


Table 9. Constituents in Ascophyllum nodosum, Fucus vesiculosus, and Laminaria digitata Ascophyllum nodosum (ppm) 176 Fucus vesiculosus (ppm) 177 Fucus vesiculosus (ppm) 176 Laminaria digitata (ppm) 29 Algin NR 41300 – 500000 NR NR Alginic acid NR NR NR 200000 – 450000 Aluminum NR 75.0 - 631.0 NR NR Arsenic NR 68.0 NR NR Ascorbic-acid NR 30.0 - 258.0 NR NR Bromine NR 150.0 NR NR Calcium 9847 3587 – 30400 11600 NR Carbohydrates NR 77290 – 655000 NR 10000 – 20000 β-carotene NR 5.0 – 40.0 NR NR Chromium NR 0.1 – 0.7 NR NR Cobalt NR 0.2 – 1.6 NR NR Fat NR 3540 – 30000 NR 10000 – 20000 Fiber NR 98000 NR NR Fiber(crude) NR 98000 NR NR Fiber(dietary) NR 482000 NR NR Fucinicacid NR 1000 NR NR Fucoidin NR 600000 NR 20000 – 40000 Fucose NR 240000 NR NR Iodine NR 64.0 – 540.0 NR 3000 – 1100 Iron 133.4 2.0 – 16.0 189.9 NR Kilocalories NR 2490 NR NR Lead NR 91.0 NR NR γ-Linolenic acid NR NR NR NR Magnesium 8678 1023 – 8670 7320 5000 – 8000 Mannitol NR NR NR 40000 – 160000 Manganese 19.6 0.9 – 7.6 82.8 NR Mercury NR 40.0 NR NR Niacin NR 6.0 – 47.0 NR NR Phosphorus NR 294.0 -2490 1935.7 NR Potassium 37810 2490 – 21,100 37450 13000 – 38000 Selenium NR 0.2 – 1.7 NR NR Silicon NR 0.9 – 7.6 NR NR Sodium 45757 6620 – 56,100 21875 9000 – 22000 Sugars NR 2360 – 20000 NR NR Tin NR 3.0 – 24.0 NR NR Water NR 882000 NR 730000 – 900000 Zinc NR 0.1 – 0.6 NR NR NR = not reported


https://phytochem.nal.usda.gov/phytochem/chemicals/show/3299


































Table 10. Sterols in several brown algae

Species Desmosterol (mg/kg)

Ergosterol (mg/kg)

Fucosterol (mg/kg)

Cholesterol (mg/kg)

Campesterol + Stigmasterol (mg/kg)

β-Sterol (mg/kg)

Brassicasterol (mg/kg)

Ssaringosterol (mg/kg)

24-ketocholesterol (mg/kg)

Totala

(mg/kg) Reference Cystoseira tamariscifolia

44.1 ± 3.4 - 5260.2 ± 14.9 500.4 ± 2.6 680.9 ± 21.4 17.0 ± 0.3 NR NR NR 6502.6 61

Fucus spiralis 37.6 ± 3.8 - 3815.1 ± 329.5 325.1 ± 13.5 183.4 ± 0.3 - NR NR NR 4361.0 61 Sargassum vulgare 47.2 ± 0.2 5.6 ± 0.4 4451.5 ± 16.7 406.3 ± 13.2 303.3 ± 18.9 15.2 ± 2.8 NR NR NR 5229.1 61 NR = not reported; - = not found a Total may not be exact due to rounding.


Table 11. Constituents of ethanol extracts of Fucus spiralis and Sargassum vulgare63 Range (if provide; ppm) Constituent Fucus spiralis extract Sargassum vulgare extract Arachidic Acid ND ND Arachidonic Acid 465.6 ± 29.0 ND Cholesterol ND 127.4 ± 11.6 Eicosapentaenoic Acid 217.0 ± 11.4 ND Fucosterol 317.6 ± 9.4 257.6 ± 43.6 γ-Linolenic Acid ND 2413.6 ± 57.6 Mannitol (Total) 1273.8 ± 34.8 394.6 ± 15.2 Myristic Acid 69.8 ± 2.7 ND Palmitic Acid 606.0 ± 20.6 340.4 ± 95.0 Phloroglucinol < LOD ND Proline 396.8 ± 96.8 117.4 ± 11.0 β-Sitosterol ND ND Stearic Acid 208.4 ± 21.4 204.0 ± 26.0 Vaccenic Acid 21,690.6 ± 1667.6 2848.6 ± 71.2 LOD = limit of detection; ND = not detected Table 12. Composition of a 50/50 water/propylene glycol extract of Laminaria japonica51 Constituent Amount

Constituent Groups (mg/g) Carbohydrate 6 Sugars 5 Proteins 2 Crude fat 2 Saturated fatty acid 1 Unsaturated fatty acid None detected

Amino Acids (mg/L) Alanine 42.3 Ammonium chloride 16.2 Arginine 20.3 Aspartic acid 424.7 Glutamic acid 689.4 Glycine 1.7 Hydroxyproline 381.4 Phosphoserine 3.7 Serine 8.6 Threonine 4.2

Minerals (mg/g) Sodium 404 Calcium 300 Potassium 1022 Magnesium 35 Iron 0.5 Zinc 0.2 Table 13. Composition of enzyme hydrolysis extracts of Laminaria japonica52 Constituent Concentration (% w/w) Laminaria japonica extract52 Ash 4.1 ± 0.1 Fat 0.6 ± 0.1 Fucose 85.9 Moisture 3.9 ± 0.8 Monosaccharides (neutral) NR Protein 4.3 ± 0.3% Sulfate 28.4 ± 2.1 NR = not reported










Table 14. Specifications of an alcohol extract of Ecklonia cava for use as a food supplement9 Parameter Specification Phlorotannin 90 ± 5.0% Dieckol 6.6% – 9.9% Moisture content < 5% Ash < 5% Insoluble substances Negative Substances not originating from E. cava Negative Viable cell count < 3000 CFU/g Staphylococcus aureus Negative Molds and yeasts < 300 CFU/g Salmonella spp. Negative Coliforms Negative Lead < 3 mg/kg Mercury < 0.1 mg/kg Cadmium < 3 mg/kg Arsenic < 25 mg/kg Iodine 150.0 – 650.0 mg/kg Sieving size > 60 (0.250 mm) CFU = colony-forming unit Table 15. Constituents of desalinated Undaria pinnatifida powder67

Constituent Amount (mg/g) Ash 147

Calcium 13.6 Copper 0.00130

Dietary fiber 532 Iron 0.107

Lipid 14 Magnesium 13.4

Protein 209 Sodium 25.4

Zinc 0.02 Table 16. Flavonoid content of brown algae species (µg/g dry weight)68

Flavonoid Undaria pinnatifida

Hizikia fusiformis

Ecklonia cava

Sargassum muticum Rutin 457 ± 6.3 - 2730 ± 190 - Quercitrin 202 ± 26 - - - Hesperidin - - 4240 ± 380 + Myricetin - - - - Morin 1020 ± 110 1010 ± 11 2360 ± 280 927 ± 30 Caffeic acid 53.6 ± 60 - - - -: not detected; + = trace amounts detected


Table 17. Allergens found in trade name mixtures containing brown algae-derived ingredients.

Allergen

Amount (ppm) Undaria Pinnatifida Cell Culture Extract (0.5-2%)178

Hydrolyzed Fucus Vesiculosus Protein (98.9%)179

Sargassum Filipendula Extract (1.3%)180

Alpha-IsoMethyl Ionone < 0.02 0.00 < 0.02 Amyl Cinnamal < 0.10 0.00 < 0.10 Anise Alcohol < 0.00 0.00 < 0.00 Benzyl Alcohol < 0.01 0.00 < 0.01 Benzyl Benzoate < 0.09 0.00 < 0.09 Benzyl Cinnamate < 0.30 0.00 < 0.30 Benzyl Salicylate < 0.06 0.00 < 0.06 Butylphenyl Methylpropional < 0.50 0.00 < 0.50 Cinnamal < 0.01 0.00 < 0.01 Cinnamyl Alcohol < 0.30 0.00 < 0.30 Citral < 1.00 0.00 < 1.00 Citronellol < 1.00 0.00 < 1.00 Coumarin < 0.00 0.00 < 0.00 Eugenol < 0.70 0.00 < 0.70 Farnesol < 0.04 0.00 < 0.04 Geraniol < 0.08 0.00 < 0.08 Hexyl Cinnamal < 0.40 0.00 < 0.40 Hydroxycintronellal <1.00 0.00 <1.00 Hydroxymethylpentyl 3-Cyclohexene carboxaldehyde

< 0.00 0.00 < 0.00

Isoeugenol < 0.06 0.00 < 0.06 Limonene < 0.05 0.00 < 0.05 Linalool < 0.00 0.00 < 0.00 Methyl 2-Octynoate < 0.20 0.00 < 0.20 Evernia prunastri < 0.02 0.00 < 0.02 Evernia furfuracea < 0.00 0.00 < 0.00 Amylcinnamyl Alcohol < 1.00 0.00 < 1.00 Table 18. Concentration of arsenic found in several brown algae species54

Species

Arsenic Concentration Arsenic Concentration

(mg/kg wet wt.) (mg/kg dry wt.) Ecklonia radiate 1054 - Hizikia fusiforme 1054 - Laminaria japonica 454 - Laminaria ochroleuca - 56.8 ± 2.469 Laminaria saccharina - 52.4 ± 2.169 Saccharina (spp) - < 0.3181 Sargassum fusiforme - 67 - 96181 Sargassum thunbergii 454 - Unidaria pinnatifida 2.8 – 4.554 < 0.3181

115 ± 969 - = no data Table 19. Arsenic -containing moieties found in various brown algae69

Arsenic-Containing Moiety Amount (mg/kg)

Laminaria ochroleuca Laminaria saccharina Sargassum fulvellum Undaria pinnatifida Arsenic III ND ND ND ND Arsenic V ND ND 69.9 ± 1.0 0.29 ± 0.03 Methylarsonate ND 0.21 ± 0.03 ND ND Dimethylarsinate 0.26 ± 0.08 0.67 ± 0.02 2.1 ± 0.1 0.13 ± 0.03 Trimethylarsine oxide ND ND ND ND Arsenobetaine 0.20 ± 0.02 0.09 ± 0.02 ND ND Phospate-sug po4 6.2 ± 0.1 6.9 ± 0.1 2.2 ± 0.1 0.30 ± 0.02 Sulfonate-sug so3 39.4 ± 1.6 30.7 ± 1.2 1.80 ± 0.10 ND Sulfate-sug so4 ND ND 9.0 ± 0.7 ND Glycerol-sug gly 2.71 ± 0.04 2.9 ± 0.1 1.2 ± 0.2 0.87 ± 0.03 Arsenocholine ND ND ND ND Inorganic arsenic ND ND 69.9 0.29 ND = not detected


Table 20. Arsenic species found in Laminaria japonica and an extract of Laminaria japonica52

Arsenic Species Amount (mg/kg)

Laminaria japonica Laminaria japonica extracta

Arsenic III ND ND Arsenic V ND ND Monomethylarsonic Acid 9.27 ± 0.96 1.35 ± 0.63 Dimethylarsinic Acid 9.23 ± 0.83 ND Arsenobetaine 34.31 ±1.21 4.77 ± 0.88 Arsenocholine 6.19 ± 2.17 ND Arsenic (sum) 59.00 ± 1.65 6.12 ± 2.005 ND = not detected a Extracted by enzyme hydrolysis, high in low-molecular-weight fucoidan

Table 21. Heavy metals and arsenic in brown algae Concentration of heavy metals and arsenic (mg/kg dry weight) Reference

Species Cadmium Lead Mercury Copper Zinc Arsenic Inorganic Arsenic

Alaria esculenta 0.22 – 7.9 0.2 – 1.9 < 0.005 - <0.071

0.39 - 4 7 - 45 <0.074 - 100 - 182

Fucus vesiculosus 1.7 11 - 12.7 89 13.5 - 157 Himanthalia elongata 0.310 – 0.326 0.203 – 0.259 0.008 – 0.016 1.14 – 1.25 48.5 – 48.7 32.9 – 36.7 0.166 – 0.245 71 Hizikia fusiforme 0.988 – 2.50 < 0.008a – 0.531 0.015 – 0.050 1.78 – 7.70 4.72 – 19.5 103 – 147 32.1 – 69.5 71 Laminaria spp. 0.085 – 1.83 < 0.008a – 0.460 0.001 – 0.005 0.91 – 2.50 10.3 – 23.2 51.7 – 68.3 0.052 – 0.443 71 Undaria pinnatifida 0.267 – 4.82 < 0.008a – 1.28 0.010 – 0.057 1.07 – 1.70 8.25 – 26.6 42.1 – 76.9 0.045 – 0.346 71 a Limit of detection. spp. = multiple species

Table 22. Heavy metal, arsenic, and iodine impurities in trade name mixtures containing brown algae species Concentration of heavy metals (ppm) Reference Trade name mixture Arsenic Cadmium Lead Nickel Silver Iodine Mercury Alaria Esculenta Extract (< 5%) in butylene glycol and water

< 5 < 3 < 5 < 2 < 5 < 10 - 183

Alaria Esculenta Extract (< 5%) in butylene glycol and water – dried before extraction

< 5 < 3 < 5 < 2 < 5 < 10 - 184

Alaria Esculenta Extract (< 5%) in Caprylic/Capric Triglycerides

< 2 < 3 < 5 < 2 < 5 < 1 < 1 185

Ascophyllum Nodosum Extract (40.5%), Halopteris Scoparia Extract (13.5%), water

1.683 < 0.010 < 0.010 - - - < 0.010 186

Cystoseira Amentacea/ Caespitosa/Brachycarpa Extracts (48%) in water

7.303 < 0.010 < 0.010 - - - < 0.010 105

Cystoseira Tamariscifolia Extract (0.5%) and Caprylic/Capric Triglycerides

- - - - - 1 - 49

Cystoseira Tamariscifolia Extract (0.5%), water, and glycerin

1.35 - - - - 1.4 - 125

Dictyopteris Polypodioides Extract (0.5%), water, and glycerin

0.809 - - - - 19 - 125

Dictyopteris Polypodioides Extract (0.5%), water, and glycerin

0.602 - - - - 19 - 125

Dictyopteris Polypodioides Extract (0.5%) and caprylic/capric triglyceride

0.051 - - - - < 9 - 125

Fucus Vesiculosus Extract, water and alcohol

< 10 - - - - - - 187

Fucus Vesiculosus Extract and sodium sulfate

< 10 - - - - - - 187

Fucus Vesiculosus Extract (< 5%) in caprylic/capric triglyceride

< 2 < 3 < 5 < 2 < 5 < 1 - 188

Fucus Vesiculosus Extract (0.5%), dipropylene glycol, and water

- - - - - < 9 - 125


Table 22. Heavy metal, arsenic, and iodine impurities in trade name mixtures containing brown algae species Concentration of heavy metals (ppm) Reference Trade name mixture Arsenic Cadmium Lead Nickel Silver Iodine Mercury Fucus Serratus Extract (44%) and water

3.691 0.011 < 0.010 - - - < 0.010 189

Fucus Spiralis Extract (1-3%), butylene glycol, water

< 2 < 3 < 5 < 2 < 5 < 10 - 190

Fucus Spiralis Extract (12%), tetraselmis chui extract (8%), and water

0.65 < 0.05 < 0.05 - - - < 0.05 191

Halidrys Siliquosa Extract (48%) in water

0.01 < 0.010 < 0.010 - - - < 0.010 65

Halopteris Scoparia Extract (0.5%), water, and dipropylene glycol

0.73 - - - - 15 - 125

Himanthalia Elongata Extract (0.5%), water, and dipropylene glycol

- - - - - < 9 - 49

Himanthalia Elongata Extract (20%), Undaria Pinnatifida Extract (30%), and water

0.510 0.010 - - - - 0.010 64

Himanthalia Elongata Extract (62%), saccharomyces cerevisiae extract (0.1%), Fucus Vesiculosus Extract (1.4%), and water

1.264 < 0.010 0.210 - - - < 0.010 192

Hizikia Fusiforme Extract, water, and butylene glycol

<10 - - - - - - 26

Laminaria Digitata Extract (0.5%), water, and sea salt

1.5 - - - - 62 - 49

Laminaria Digitata Extract (0.5%), water, dipropylene glycol

2.37 - - - - 87 - 49

Laminaria Digitata Extract (0.5%) and water

< 10 - - - - 550 ± 150 - 49


19.06 - - - - 192 - 49


2.69 - - - - 41 - 125

Laminaria Digitata Extract (< 5%) in caprylic/capric triglyceride

< 2 < 3 < 5 < 2 < 5 < 300 - 193

Laminaria Digitata Extract (1.5 – 2.5%) in water and propylene glycol

< 5 < 10 < 5 < 2 < 5 < 400 - 194

Laminaria Japonica Extract (7%), Nereocystis Leutkeana Extract (7%), Macrocystis Pyrifera Extract (7%), and pentaerythrityl tetraethylhexanoate

< 2 < 1 <10 - - - - 195

Laminaria Hyperborea Extract (<5%)

< 2 < 3 < 5 < 2 < 5 < 320 - 196

Laminaria Ochroleuca Extract (<5%), caprylic/capric triglyceride, and tocopherols

< 0.025 < 0.025 < 0.025 - - - < 0.025 197

Laminaria Saccharina, water, and propylene glycol

< 2 < 3 < 5 < 2 < 5 < 200 < 1 198

Laminaria Saccharina Extract in water and propylene glycol

< 2 < 3 < 5 < 2 < 5 < 200 < 1 198

Laminaria Saccharina Extract in water and butylene glycol

< 2 < 3 < 5 < 2 < 5 < 200 < 1 199

Lessonia Nigrescens Extract (12%), water, and butylene glycol

2.628 0.050 < 0.010 - - - 0.012 200

Macrocystis Pyrifera (1-3%) in water and methylpropanediol

< 5 < 10 < 5 < 2 < 5 < 5 - 35

Pelvetia Canaliculata Extract (44%) and water

2.383 < 0.010 < 0.010 - - - < 0.010 201

Pelvetia Canaliculata Extract (0.5 – 3%) in butylene glycol and water

< 3 < 3 < 5 < 2 < 5 < 10 - 202

Pelvetia Canaliculata Extract (5.5 – 9% dry extract) in propylene glycol and water

< 2 < 3 < 5 < 2 < 5 < 10 - 203


Table 22. Heavy metal, arsenic, and iodine impurities in trade name mixtures containing brown algae species Concentration of heavy metals (ppm) Reference Trade name mixture Arsenic Cadmium Lead Nickel Silver Iodine Mercury Pelvetia Canaliculata and Laminaria Digitata (5.5 – 9% dry extract) extracted in propylene glycol with panthenol

< 5 < 3 < 5 < 2 < 5 < 100 - 204

Pelvetia Canaliculata and Laminaria Digitata (5.5 – 9% dry extract) extracted in butylene glycol with preservatives

< 5 < 10 < 5 < 2 < 5 < 100 - 205

Pelvetia Canaliculata and Laminaria Digitata (5.5 – 9% dry extract)extracted in butylene glycol without preservatives

< 5 < 10 < 5 < 2 < 5 < 100 - 202

Phyllacantha Fibrosa Extract (0.5%) and water

11.35 - - - - 140 - 49

Phyllacantha Fibrosa Extract (0.5%) and water

11.35 - - - - 97 - 125

Sargassum Glaucescens Extract (20%), water (79%), phenoxyethanol (1%)

< 2.5 - < 1 < 230 - - - 206

Sargassum Muticum Extract (46%) and water

1.562 < 0.010 < 0.010 - - - < 0.010 207

Undaria Pinnatifida Cell Culture Extract (0.5%)

< 2 < 1 < 10 - - - - 208

Sphacelaria Scoparia Extract (0.5%)

0.73 - - - - 15 - 49

Undaria Pinnatifida Extract (0.5%) in glycerin and water

0.837 - - - - <1 - 125

Undaria Pinnatifida Extract (0.5%) in water and propylene glycol

< 5 < 10 < 5 < 2 < 5 < 1 < 1 209

Undaria Pinnatifida Extract (0.5%) in caprylic/capric triglyceride

< 0.025 - - - - 1.2 - 125

Undaria Pinnatifida Extract (0.5%) in caprylic/capric triglyceride

< 2 < 3 < 5 < 2 < 5 < 1 < 1 210

- = not reported Table 23. Frequency (2019) and concentration of use (2015 - 2016) according to duration and exposure of brown algae-derived ingredients75-77,211 Use type # Uses Max. Conc. (%) # Uses Max. Conc.(%) # Uses Max. Conc.(%) # Uses Max.Conc. (%)

Agarum Cribrosum Extract Alaria Esculenta Extract Ascophyllum Nodosum

Extract Ascophyllum Nodosum

Powder Total/range 1 0.012 41 0.0005-0.05 140 0.0000004-0.2 5 NR Duration of usea Leave-on 1 0.012 41 0.0005-0.05 111 0.0000004-0.2 3 NR Rinse-off NR NR NR 0.0015 29 0.00004-0.0032 1 NR Diluted for (bath) use NR NR NR NR NR NR 1 NR Exposure type Eye area NR NR 12 NR 17 0.025-0.2 NR NR Incidental Ingestion NR NR 3 NR NR NR NR NR Incidental Inhalation-Spray 1b NR 6a; 6b 0.0005a 23a; 62b 0.002a 2a NR Incidental Inhalation-Powder 1b NR 5; 6b 0.0015-0.05c 1; 62b 0.0000004-0.03c NR NR Dermal Contact 1 0.012 37 0.0005-0.05 124 0.0000004-0.2 5 NR Deodorant (underarm) NR NR NR NR NR NR NR NR Hair-Non-Coloring NR NR 1 NR 13 0.00005-0.002 NR NR Hair- Coloring NR NR NR NR NR NR NR Nail NR NR NR NR 3 0.000065-0.02 NR NR Mucous Membrane NR NR 3 NR 6 0.00004 1 NR Baby Products NR NR NR NR NR NR NR NR


Table 23. Frequency (2019) and concentration of use (2015 - 2016) according to duration and exposure of brown algae-derived ingredients75-77,211 Use type # Uses Max. Conc. (%) # Uses Max. Conc.(%) # Uses Max. Conc.(%) # Uses Max.Conc. (%) Cladosiphon Okamuranus

Extract Dictyopteris Polypodioides

Extractd Ecklonia Cava Extract Ecklonia Radiata Extract Total/range 10 0.005-0.05 6 0.01 18 0.0001 82 0.005-0.0051 Duration of use Leave-on 9 0.025-0.05 5 0.01 15 0.0001 13 0.0051 Rinse-off 1 0.005 1 NR 3 NR 69 0.005 Diluted for (bath) use NR NR NR NR NR NR NR NR Exposure type Eye area 1 0.025 NR NR 1 NR NR NR Incidental Ingestion NR NR NR 0.01 NR NR NR NR Incidental Inhalation-Spray 4a; 3b NR 4a; 1b NR 5a; 8b NR 7; 6a 0.0051 Incidental Inhalation-Powder 3b 0.025b 1b NR 8b; 1c NR NR NR Dermal Contact 10 0.005-0.05 6 NR 17 NR NR NR Deodorant (underarm) NR NR NR NR NR NR NR NR Hair-Non-Coloring NR NR NR NR 1 NR 82 0.0051 Hair- Coloring NR NR NR NR NR NR NR NR Nail NR NR NR NR NR 0.001 NR NR Mucous Membrane NR NR NR 0.01 NR NR NR NR Baby Products NR NR NR NR 1 NR NR NR Fucus Serratus Extract Fucus Vesiculosus Fucus Vesiculosus Extract Fucus Vesiculosus Powder Total/range 8 0.00001-0.05 NR 0.0003-0.0051 291 0.00002-5 4 NR Duration of use Leave-on 8 0.05 NR 0.00098-0.0051 192 0.000032-5 1 NR Rinse-off NR 0.00001-0.05 NR 0.0003 90 0.00002-5 2 NR Diluted for (bath) use NR NR NR NR 9 0.0001-5 1 NR Exposure type Eye area 8 0.05 NR NR 5 0.01-5 NR NR Incidental Ingestion NR NR NR NR NR 0.0005 NR NR Incidental Inhalation-Spray 3a; 4b NR NR 0.00098 3; 81a;

78b 0.00018-0.12;

0.0001-0.1a 1b NR

Incidental Inhalation-Powder 4b 0.05c NR NR 78b 0.000032-.05c 1b NR Dermal Contact 8 NR NR 0.00098-0.0051 260 0.00002-5 4 NR Deodorant (underarm) NR NR NR NR NR NR NR NR Hair- Non-Coloring NR 0.000010 NR 0.0003 29 0.0001-5 NR NR Hair- Coloring NR NR NR NR NR 0.0001-0.001 NR NR Nail NR NR NR NR NR 0.02 NR NR Mucous Membrane NR NR NR NR 39 0.00002-5 1 NR Baby Products NR NR NR NR NR NR NR NR

Himanthalia Elongata Extract Laminaria Cloustoni

Extract Laminaria Digitata

Extract Laminaria Digitata Powder Total/range 14 0.2 15 NR 310 0.00004-5 18 40 Duration of use Leave-on 11 0.2 11 NR 229 0.0001-5 2 40 Rinse-off 3 NR 4 NR 74 0.00004-5 13 NR Diluted for (bath) use NR NR NR NR 7 0.1-5 3 NR Exposure type Eye area 1 NR 1 NR 20 0.0035-0.5 NR NR Incidental Ingestion NR NR NR NR 2 NR NR NR Incidental Inhalation-Spray 2a; 7b NR 5a; 4b NR 3; 71a;

88b 0.0007; 0.0035-

5a 1b NR

Incidental Inhalation-Powder 7b NR 4b NR 2; 88b 0.0001-0.1c 1b 40b Dermal Contact 11 0.2 15 NR 266 0.0001-5 15 40 Deodorant (underarm) NR NR NR NR NR NR NR NR Hair- Non-Coloring 3 NR NR NR 36 0.0007-5 3 NR Hair- Coloring NR NR NR NR 1 0.00004-0.0007 NR NR Nail NR NR NR NR NR NR NR NR Mucous Membrane NR NR NR NR 23 0.06-5 4 NR Baby Products NR NR NR NR NR NR NR NR


Table 23. Frequency (2019) and concentration of use (2015 - 2016) according to duration and exposure of brown algae-derived ingredients75-77,211 Use type # Uses Max. Conc. (%) # Uses Max. Conc.(%) # Uses Max. Conc.(%) # Uses Max.Conc. (%)

Laminaria Hyperborea Extract Laminaria Japonica

Extract Laminaria Ochroleuca

Extract Laminaria Saccharina

Extract Total/range 14 0.03 98 0.005-5 54 0.000024-0.63 136 0.00001-0.54 Duration of use Leave-on 14 0.03 81 0.0005-5 48 0.00017-0.63 89 0.000092-0.54 Rinse-off 1 NR 17 0.0005-5 6 0.000024-0.017 47 0.00001-0.51 Diluted for (bath) use NR NR NR 0.011-5 NR NR NR NR Exposure type Eye area NR NR 4 0.0005-0.007 7 0.0034-0.63 NR 0.000092-0.019 Incidental ingestion NR NR 1 NR 1 NR NR NR Incidental Inhalation-Spray 2; 7a; 3b NR 14a; 40b 0.3-5a 16a; 12b 0.017; 0.017a 42a; 20b 0.001-0.005 Incidental Inhalation-Powder 3b 0.03c 3; 2c; 40b 0.0035; 0.0055-

5c 3; 12b 0.0005-0.17c 20b 0.0008; 0.000092-0.1c

Dermal Contact 14 0.03 92 0.0005-5 53 0.000024-0.63 124 0.000092-0.54 Deodorant (underarm) NR NR NR NR NR NR NR 0.15e

Hair- Non-Coloring 1 NR 2 0.0005-0.3 NR 0.017 12 0.00001-0.045 Hair- Coloring NR NR NR NR NR 0.017 NR Nail NR NR 2 NR NR NR NR 0.001 Mucous Membrane 1 NR 6 0.011-5 3 NR 4 0.51 Baby Products NR NR 2 NR NR NR NR NR

Lessonia Nigrescens Extract Macrocystis Pyrifera

(Kelp) Macrocystis Pyrifera

(Kelp) Extract Macrocystis Pyrifera (Kelp)

Protein Total/range NR 0.032 2 NR 199 0.00005-36.4 3 NR Duration of use Leave-on NR NR 1 NR 114 0.0002-36.4 1 NR Rinse-off NR 0.032 1 NR 81 0.00005-5 2 NR Diluted for (bath) use NR NR NR NR 4 0.0051-1 NR NR Exposure type Eye area NR NR NR NR 5 0.007-36.4 NR NR Incidental Ingestion NR NR NR NR NR 0.079 NR NR Incidental Inhalation-Spray NR NR 1a NR 10; 40a;

27b 0.042-0.79;

0.0036-5a; 0.17b NR NR

Incidental Inhalation-Powder NR NR NR NR 2; 27b 0.0035; 0.001-33.3c; 0.17b NR NR

Dermal Contact NR 0.032 2 NR 134 0.00005-36.4 3 NR Deodorant (underarm) NR NR NR NR NR NR NR NR Hair- Non-Coloring NR NR NR NR 56 0.001-5 NR NR Hair- Coloring NR NR NR NR 4 NR NR Nail NR NR NR NR 5 0.0002-0.0011 NR NR Mucous Membrane NR NR 1 NR 39 0.0051-5 1 NR Baby Products NR NR NR NR 1 NR NR NR

Pelvetia Canaliculata Extract Sargassum Filipendula

Extract Sargassum Fusiforme

Extract Sargassum Muticum Extract Total/range 47 0.00002-0.018 46 0.0001-1.2 17 NR 1 0.01-0.076 Duration of use Leave-on 34 0.00002-0.018 14 0.0001-1.2 13 NR NR 0.076 Rinse-off 13 0.00004-0.0018 32 0.002-0.29 4 NR 1 0.01 Diluted for (bath) use NR NR NR NR NR NR NR NR Exposure typea Eye area 6 0.00002-0.0007 2 NR NR NR NR 0.076 Incidental Ingestion NR NR NR NR NR NR NR NR Incidental Inhalation-Spray 1; 18a; 8b 0.00004-0.0007;

0.002-0.0035a 3; 5a; 1b 0.0001a 7a; 4b NR NR NR

Incidental Inhalation-Powder 8b 0.002-0.018c 1b 0.8c 4b; 1c NR NR NR Dermal Contact 19 0.00002-0.018 16 0.002-1.2 17 NR 1 0.076 Deodorant (underarm) NR NR NR NR NR NR NR NR Hair- Non-Coloring 24 0.00004-0.0025 7 0.0001-0.29 NR NR NR NR Hair- Coloring 1 0.0000-0.0007 23 0.011-0.29 NR NR NR NR Nail NR NR NR NR NR NR Mucous Membrane 1 NR NR NR NR NR NR NR Baby Products NR NR NR NR 1 NR NR NR


Table 23. Frequency (2019) and concentration of use (2015 - 2016) according to duration and exposure of brown algae-derived ingredients75-77,211 Use type # Uses Max. Conc. (%) # Uses Max. Conc.(%) # Uses Max. Conc.(%) # Uses Max.Conc. (%)

Sargassum Vulgare Extract Sphacelaria Scoparia

Extract Undaria Pinnatifida

Extract Undaria Pinnatifida Powder Total/range NR 0.0075-0.016 8 0.016 90 0.00001-5 NR 0.1 Duration of use Leave-on NR 0.009-0.016 6 0.016 76 0.00001-5 NR NR Rinse-off NR 0.0075 2 NR 14 0.0001-5 NR 0.1 Diluted for (bath) use NR NR NR NR NR 0.0001 NR NR Exposure type Eye area NR 0.011 NR NR 4 NR NR NR Incidental Ingestion NR NR NR NR NR NR NR NR Incidental Inhalation-Spray NR 0.009a 1a; 4c NR 18a; 42b 0.002a NR NR Incidental Inhalation-Powder NR 0.011c 4c NR 2; 42b; 3c 0.00001-5;

0.00001-5c NR NR

Dermal Contact NR 0.011-0.016 8 0.016 80 0.00001-5 NR 0.1 Deodorant (underarm) NR NR NR NR NR NR NR NR Hair- Non-Coloring NR 0.0075-0.009 NR NR 10 0.002-5 NR NR Hair- Coloring NR NR NR NR NR NR NR NR Nail NR NR NR NR NR NR NR NR Mucous Membrane NR NR 2 NR 4 0.0001 NR NR Baby Products NR NR NR NR 4 NR NR NR

Nereocystis Luetkeana Extract Sargassum Fulvellum

Extract Saccharina Longicruris

Extract Halidrys Siliquosa Extract

Total/range 6 NR 2 NR 2 2 NR 0.029 – 0.29 Duration of use Leave-on 6 NR 2 NR NR NR NR 0.29 Rinse-off 0 NR NR NR 2 2 NR 0.029 Diluted for (bath) use 0 NR NR NR NR NR NR NR Exposure type Eye area NR NR NR NR NR NR NR 0.29 Incidental Ingestion NR NR NR NR NR NR NR NR Incidental Inhalation-Spray NR NR 2b NR NR NR NR NR Incidental Inhalation-Powder 2 NR 2b NR NR NR NR 0.29c Dermal Contact 6 NR 2 NR NR NR NR 0.029–0.29 Deodorant (underarm) NR NR NR NR NR NR NR NR Hair- Non-Coloring NR NR NR NR 2 2 NR NR Hair- Coloring NR NR NR NR NR NR NR NR Nail NR NR NR NR NR NR NR NR Mucous Membrane NR NR NR NR NR NR NR NR Baby Products NR NR NR NR NR NR NR NR NR = Not Reported; NS = Not Surveyed; Totals = Rinse-off + Leave-on + Diluted for Bath Product Uses. Note: Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure type uses may not equal the sum total uses. a It is possible these products may be sprays, but it is not specified whether the reported uses are sprays. b Not specified whether a powder or a spray, so this information is captured for both categories of incidental inhalation. c It is possible these products may be powders, but it is not specified whether the reported uses are powders. d Frequency of use and concentration of use were reported under the INCI name Dictyopteris Membranacea Extract (Retired). e Not spray.


Table 24. Brown algae-derived ingredients with no reported uses in the VCRP or the Council survey75-77 Ascophyllum Nodosum Cladosiphon Novae-Caledoniae Extract Cystoseira Amentacea/Caespitosa / Branchycarpa Extract Cystoseira Baccata Extract Cystoseira Balearica Extract Cystoseira Caespitosa Extract Cystoseira Compressa Extract Cystoseira Compressa Powder Cystoseira Tamariscifolia Extract Dictyota Coriacea Extract Ecklonia Cava Extract Ecklonia Cava Water Ecklonia Kurome Extract Ecklonia Kurome Powder Ecklonia Maxima Extract Ecklonia Maxima Powder Ecklonia/Laminaria Extract Eisenia Arborea Extract Fucus Spiralis Extract Halidrys Siliquosa Extract Himanthalia Elongata Powder Hizikia Fusiforme Extract Hizikia Fusiformis Callus Culture Extract Hizikia Fusiformis Water Hizikia Fusiformis Water

Hydrolyzed Ecklonia Cava Extract Hydrolyzed Fucus Vesiculosus Extract Hydrolyzed Fucus Vesiculosus Extract Hydrolyzed Fucus Vesiculosus Protein Laminaria Diabolica Extract Laminaria Japonica Powder Laminaria Longissima Extract Laminaria Longissima Extract Lessonia Nigrescens Powder Macrocystis Pyrifera (Kelp) Blade/Pneumatocyst/Stipe Juice Extract Macrocystis Pyrifera (Kelp) Juice Macrocystis Pyrifera (Kelp) Juice Pelvetia Siliquosa Extract Phyllacantha Fibrosa Extract Saccharina Angustata Extract [Laminaria Angustata Extract (Retired)] Saccharina Japonica Extract [Laminaria Ochotensis Extract (Retired)] Sargassum Glaucescens Extract Sargassum Horneri Extract Sargassum Pallidum Extract Sargassum Siliquastrum Extract Sargassum Thunbergii Extract Undaria Peterseniana Extract Undaria Pinnatifida Cell Culture Extract Undaria Pinnatifida Leaf/Stem Extract Undaria Pinnatifida Root Powder

Table 25. GRAS brown algae-derived ingredients Species Functional Use in Food CFR Citation Hizikia fusiforme Spices, seasoning, flavoring 21CFR184.1120 Laminaria spp. Natural substances; solvent-free natural

extractives 21CFR582.30; 21CFR582.40

Laminaria claustonia Spices, seasoning, flavoring; dietary supplement

21CFR184.1120; 21CFR172.365

Laminaria digitata Spices, seasoning, flavoring; dietary supplement

21CFR184.1120; 21CFR172.365

Laminaria japonica Spices, seasoning, flavoring 21CFR184.1120 Laminaria longissima Spices, seasoning, flavoring 21CFR184.1120 Laminaria saccharina Spices, seasoning, flavoring; dietary

supplement 21CFR184.1120; 21CFR172.365

Nereocystis spp. Natural substances; solvent-free natural extractives

21CFR582.30; 21CFR582.40

Macrocystis pyrifera Spices, seasoning, flavoring; dietary supplement

21CFR184.1120; 21CFR172.365

Undaria pinnatifida Spices, seasoning, flavoring 21CFR184.1120


Table 26. Brown algae species used in food products16 Species Methods of consumption Reference Alaria esculenta Eaten either fresh or cooked 16 Ascophyllum nodosum Eaten either fresh or cooked 212 Cladosiphon okamuranus Eaten fresh and in seaweed salads 16 Ecklonia cava Used in addition to Hizikia as pigment replacer; typically cooked into stir fries 16 Fucus vesiculosus Eaten as a vegetable or condiment 87 Fucus serratus Eaten as a vegetable or condiment 87 Hizikia fusiforme Steamed to remove phlorotannins, and cooked into stir fries; used as a spice 16 Himanthalia elongata Eaten dried or pickled 213,214 Laminaria angustata (also known as Saccharina angustata)

Typically cooked in soups; can be powdered and added to sauces and soups; used in tea 16

Laminaria digitata Eaten dried, fresh, or cooked 212 Laminaria japonica Typically cooked in soups; can be powdered and added to sauces and soups; used in tea 16 Laminaria longissima Typically cooked in soups; can be powdered and added to sauces and soups; used in tea 16 Laminaria ochotensis Typically cooked in soups; can be powdered and added to sauces and soups; used in tea 16 Laminaria ochroleuca Eaten dried, fresh, or cooked 215 Laminaria saccharina Eaten dried, fresh, or cooked 212 Macrocystis pyrifera Used as spices, seasonings 16 Undaria pinnatifida Eaten raw in dehydrated form; used in instant foods such as noodles and soups; used as spice,

seasoning 16


Table 27. Acute oral toxicity studies

Ingredient Animals No./Group Vehicle Concentration/Dose/Protocol LD50/Results Reference ORAL

Ascophyllum Nodosum Extract Sprague-Dawley rats

NR NR OECD TG 401 LD50 > 2000 mg/kg 91

Cystoseira Compressa Extract (methanol, hexane, and chloroform extracts)

Albino mice 2 Not specified Up to 2000 mg/kg by gavage. Observed for 24 h. There were no mortalities or clinical signs for any of the extracts.

62

Ecklonia Cava Extract (alcohol extract)

Sprague-Dawley (Crl:DC(DS)) rats

10/sex Not specified 2000 mg/kg by gavage. Observed for 2 weeks. There were no mortalities. Clinical signs were soft stools, diarrhea, mucus stools, compound-colored feces, and soiled perineal region from the day of administration until day 2.

9

Ecklonia Cava Extract (enzyme extract)

SD rats 5/sex Distilled water 0 or 3000 mg/kg by oral gavage. Rats were observed for 14 days.

No abnormal changes in body weights, clinical signs, or mortalities were observed. Necropsy results showed no macroscopic lesions in any organs of treatment group.

92

Ecklonia Cava Extract (enzyme extract)

Beagle dogs 2/sex Distilled water 3000 mg/kg by oral gavage in two equally divided doses approximately 6 h apart. Dogs were observed for 14 days.

No abnormal changes in body weights, clinical signs, or mortalities were observed. Necropsy results showed no macroscopic lesions in any organs of treatment group.

92

Fucus Vesiculosus Extract (28.8% polyphenols)

Swiss mice 7/sex 1% carboxymethyl-cellulose

1000 - 2000 mg/kg OECD TG 425 Administered by gavage. An Irwin test (determines the general effects of a test substance on the central nervous system and physiological functions) was performed at 1 and 5 h after administration of the extracts to detect motor, respiratory, temperature, circulatory, behavior, or other alterations. Mice were observed for 7 days.

LD50: Males = 1000 mg/kg; females = between 1000 and 2000 mg/kg

93


Swiss mice 7/sex 1% carboxymethyl-cellulose

200 - 750 mg/kg OECD TG 425 Administered by gavage. Irwin test was performed at 1 and 5 h after administration of the extracts to detect motor, respiratory, temperature, circulatory, behavior, or other alterations. Mice were observed for 7 days.

LD50: Males = 500 mg/kg; females = < 750 mg/kg 93


Sprague-Dawley rats

7/sex 1% carboxymethyl-cellulose

1000 - 2000 mg/kg OECD TG 425 Administered by gavage. Irwin test was performed at 1 and 5 h after administration of the extracts to detect motor, respiratory, temperature, circulatory, behavior, or other alterations. Rats were observed for 7 days.

LD50: Males and females = between 1000 and 2000 mg/kg

93


Table 27. Acute oral toxicity studies

Ingredient Animals No./Group Vehicle Concentration/Dose/Protocol LD50/Results Reference Fucus Vesiculosus Extract (18% polyphenols plus 0.0012% fucoxanthin)

Sprague-Dawley rats

7/sex 1% carboxymethyl-cellulose

1000 - 2000 mg/kg OECD TG 425 Administered by gavage. Irwin test was performed at 1 and 5 h after administration of the extracts to detect motor, respiratory, temperature, circulatory, behavior, or other alterations. Rats were observed for 7 days.

LD50: Males and females = > 2000 mg/kg 93

Laminaria Digitata Extract (≤ 10%), artemisia vulgaris extract (≤ 10%), phenoxyethanol (0.8%), and water

Wistar rats 5/sex Feed or water 20%; administered via food or water ad-libitum No significant changes were reported for each of the 10 rats tested. LD50: Males and females = > 5 g/kg

94

Sargassum Fulvellum Extract (dichloromethane, ethanol, and water extracts)

BALB/c mice 5 Tween-80 (5%) 5000 mg in 10 mL vehicle by gavage. Observed for 2 weeks.

There were no mortalities. Most of the mice reacted immediately by perpetual gagging, jumping, sleeping, scaling, and writhing for 5–10 min.

50

Sargassum Thunbergii Extract BALB/c mice 5 Tween-80 (5%) 5000 mg in 10 mL vehicle by gavage. Observed for 2 weeks.

There were no mortalities. Most of the mice reacted immediately by perpetual gagging, jumping, sleeping, scaling, and writhing for 5–10 min.

50

OECD TG = Organisation for Economic Co-operation and Development Test Guideline

Table 28. Oral repeated dose studies

Test Article

Extraction Solvent/Method or Composition Animals (n) Study Duration Vehicle Dose / Concentration Results Reference

Short-Term Ascophyllum nodosum Dried Topigs Hybrid

X Piétrain weanling pigs (20)

23 days Feed 0, 2.5, 5.0, or 10.0 g/kg feed (0.25%, 0.5%, or 1.0%)

There were no adverse effects from treated feed. There were no effects on weight gain, feed consumption. Digestion characteristics were similar to controls (pH, fresh matter weight, and dry matter content), except for pH of part of the intestine was increased in the high-dose group (6.28 vs.5.96).

95

Ascophyllum nodosum Freeze-dried and powdered

Male Sprague-Dawley rats (6)

4 weeks Feed 0, 5%, 10%, or 15% in feed Food intake, weight gain, and serum enzyme (alanine transaminase and aspartate transaminase) levels indicated that seaweed diets were well tolerated.

45

Ecklonia Cava Extract Alcohol extract Male ICR mice (10)

4 weeks None 0, 1.25, 2.5 or 5 mg/d Mice were fed high fat diet (20% fat) or normal diet (5% to 10% fat). After 1 week, mice in high fat diets were administered Ecklonia Cava Extract by gavage while continuing on the high fat diet.

There were no mortalities. There was a dose-dependent lower body weight of ~ 12% - ~ 16% in the mice administered the extract compared to control group. Triglycerides, total cholesterol and LDL cholesterol were decreased in all treated groups. Liver enzymes (GPT and GOT), BUN, and creatinine values in serum were similar to controls. No data on feed consumption provided.

96



Test Article


Ecklonia Cava Extract Enzyme extract SD rats (5/sex) 14 days Water 0, 1000, 2000, or 5000 mg/kg by gavage

- There were no mortalities. No dose-related clinical abnormalities or body weight changes. - Macroscopic examination did not reveal any treatment-related abnormal lesions in males or females at necropsy; although redness in thymus, red spot in lung, and congestion and red spot in cervical lymph node were sporadically observed without a dose-dependent relationship. - Females in the 2000 and 5000 mg/kg groups had decreases in absolute and relative left ovary weights relative to control group and decreases in absolute brain weights were observed in females in 5000 mg/kg group.

92

Ecklonia Cava Extract Alcohol extract Sprague-Dawley (Crl:CD(SD)) rats (5/sex)

4 weeks None 0, 500, 1000, or 2000 mg/kg/d by gavage.

- Compound-colored stools were observed in all rats in all dosing groups starting from day 1 of dosing. Salivation after dosing was observed sporadically in 1 female in the 1000 mg/kg/d group and in 2 males and 2 females in the 2000 mg/kg/d group on days 5 to 17 of dosing. - In clinical chemical investigations in 2000 mg/kg/d group, increases in ALT, and decreases in total protein, triglycerides and glucose were observed in males. Absolute and relative liver weights and absolute kidney weights were increased in males in 2000 mg/kg/d group. In females, relative heart weights were decreased in 1000 and 2000 mg/kg/d groups. There were no differences between study groups concerning body weight. Histopathologically, atrophy of periportal hepatocytes in livers was detected in male rats in 2000 mg/kg/d group.

9

Ecklonia Cava Extract Alcohol extract Beagle dogs (2/sex)

8 days 2-week observation period

Capsule Day 1, 100 mg/kg; Day 4, 300 mg/kg; and Day 8, 1000 mg/kg

There were no mortalities. Compound-colored stools were observed in all dogs in 300 and 1000 mg/kg groups. Vomiting was observed in 1 male and 1 female dog when treated at 1000 mg/kg.

9


Ethanol (30% - 35% aq)

Sprague-Dawley rats (7/sex)

4 weeks 1% CMC 0, 200, or 750 mg/kg/d by gavage

- There were no mortalities. -Males: body and most organ weights were similar to controls. Livers had an increase weight (21%) at necropsy. - Females: body and organ weights were similar to controls.

93


Ethanol (50% - 70% aq.)

Sprague-Dawley rats (7/sex)

4 weeks 1% CMC 0, 200, or 750 mg/kg/d by gavage

- There were no mortalities. - Males: body and most organ weights were similar to controls. Livers had an increase weight (25%) at necropsy. - Females: body and organ weights were similar to controls.

93

Laminaria Japonica Extract

Ethanol extract Sprague-Dawley rats (6)

6 weeks Not clear (probably daily gavage)

0, 100, 200, or 400 mg/kg starting after 6 weeks of a 12-week high-fat diet

- There were no mortalities. - Treatment groups had decreased the body weight gain, fat-pad weights, and serum and hepatic lipid levels in high-fat-induced obese rats. Histological analysis showed that treated groups had decreased number of lipid droplets and size of adipocytes compared to untreated high-fat diet group.

46



Test Article


Subchronic Oral Cladosiphon Okamuranus Extract

hydrolyzing in HCl Wistar Rats (12/group)

3 months Water 300, 600, 1299, 2400, 4000 mg/kg bw/d by gavage

A dose-dependent increase in clotting time and decrease in alkaline phosphatase (ALP) was noted in high doses. No significant differences compares to control. No treatment-related changes in organ weights reported. No abnormalities is morphology of brain, thymus, lungs, heart, spleen, liver, adrenal glands, kidneys, testes, thyroids, prostate gland, uterus or ovaries.

47

Ecklonia Cava Extract Alcohol extract Sprague–Dawley (Crl:CD(SD)) rats (10/sex;5 additional in control and high-dose groups)

13 weeks 4-week recovery period for 5 rats in control and high-dose group

Water 0, 375, 750, or 1500 mg/kg/d - Compound-colored stools in all dose levels; not considered to be of toxicological significance. -At 750 and 1500 mg/kg/d, BUN was decreased in males, glucose was decreased in females, and neutrophil counts were increased in females, compared to controls. Sporadic salivation occurred in females. - At 1500 mg/kg/d, incidence of salivation in females increased and occurred in male rats. Salivation was mainly observed after gavage, but to some degree also before. It was considered by authors to be a temporary sign caused by the test substance, since it was no longer evident later in the day. Number of rats with salivation increased with study duration. -At 1500 mg/kg/d, males and females had a lower body weight (11.7% and 8.7%, respectively) at end of study compared to controls (not statistically significant). This effect was dose related, appearing to a minor degree also at lower dose levels. Body weight effects were more pronounced in recovery group in both sexes. Feed consumption was not decreased. Blood chemistry analyses showed increases of phosphorus and ALT concentrations and a decrease of triglycerides in males, and a decrease of glucose in females, compared to controls. Prothrombin time was increased in males compared to controls. These changes were not evident after recovery period. There were no compound related findings in histopathological investigations including liver.

9

Ecklonia Cava Extract Enzyme extract SD rats (5/sex) 13 weeks Water 0, 500, 1000, 2000, or 3000 mg/kg by gavage

- There were no mortalities. None of groups had any dose-related clinical abnormalities or body weight changes. - Urinalysis and hematological analysis showed no treatment-related adverse effects. - Serum biochemistry and organ weights showed sporadic changes. However, sporadic changes might not have any relationship with treatment because these changes were very minimal within physiologically acceptable ranges without consistency between male and female rats. - Gross visual and macroscopic changes were not observed in organs of treated rats. Histopathological examination of sampled organs revealed a few spontaneous lesions which might be unrelated to treatment because there was no difference in incidence between control and treatment groups.

92

Chronic Oral Laminaria Japonica Powder

Dried and powdered Male CDF1 mice (6)

Life time Feed 0, 2%, 5% Mean lifespans were similar in all groups: 907 ± 135, 746 ± 183, and 851 ± 225 days for 0, 2%, and 5%, respectively.

48



Test Article


Undaria Pinnatifida Extract

Filtered aqueous extract of powdered stems and thick leaves

Female Sprague-Dawley (SD) rats (12)

32 weeks Drinking water

1.5 g in 1000 mL water There were no mortalities. Body weight changes were similar between groups.

97

Undaria Pinnatifida Powder

Dried and ground Female SD rats (5)

36 weeks Feed 0, 1.0%, or 5.0% There were no mortalities. Body weight changes, thyroid weights, and T4 levels were similar between groups.

98

ALP = alkaline phosphatase; ALT = alanine aminotransferase; AMP = adenosine monophosphate; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CMC = carboxymethylcellulose; GOT = glutamic oxaloacetic transaminase; GPT = glutamic pyruvic transaminase; HDL = high-density lipoprotein; IgA = immunoglobulin A; IgG = immunoglobulin G; IgM = immunoglobulin M; LDL = low-density lipoprotein; MCHC = mean corpuscular hemoglobin concentration; T4 = thyroxin

Table 29. Genotoxicity studies Ingredient/Test Article

Extraction Solvent/ Method

Concentration/ Vehicle Procedure Test System Results Reference

In Vitro Ascophyllum Nodosum Extract

Not specified Not specified Ames assay performed according to OECD TG 471. No other details provided.

Not specified Non-mutagenic. 91

Ascophyllum Nodosum Extract

Not specified 50, 150, 500, 1500, or 5000 µg/plate; in water

Ames assay, with and without metabolic activation in accordance with OECD TG 471 (bacterial reverse mutation test). Negative control: histidine; positive control: 4-nitroquinoline-N-oxide, 3-methylmethane sulphonate, 2-aminoanthracene, and sodium azide. There was no solvent control.

S. typhimurium (strains TA97, TA98, TA100, TA102, and TA1535)

Not genotoxic in all strains 6


Not specified 150, 500, 1500, or 5000 µg/mL; in water

Mammalian cell gene mutation test accordance with OECD TG 476 (in vitro mammalian cell gene mutation test) with and without metabolic activation. Positive control without metabolic activation: ethylmethanesulphonate, with metabolic activation: BaP

CHO; K1 sub clone CHO K1

Increased mutant frequencies at 1500 and 5000 µg/mL without metabolic activation; no increase in mutation frequencies at lower concentrations. No increase in mutation frequencies at any concentration with metabolic activation.

6


Not specified With metabolic activation: 0.63, 1.25, 2.5, or 5 mg/mL; without metabolic activation: 1.25, 2.5, or 5 mg/mL

Chromosome aberration assay in accordance with OECD TG 487 (in vitro mammalian chromosome aberration test) with and without metabolic activation. Negative control: medium (serum free cell culture medium); positive controls: CPA, MMC, and colchicine

Human lymphocytes Not genotoxic 6


http://www.thefreedictionary.com/Adenosine+Monophosphate





Not specified Experiment I: With metabolic activation: 1.25, 2.5, or 5 mg/mL; without metabolic activation: 1.25, 2.5, or 5 mg/mL Experiment II: without metabolic activation: 0.63, 1.25, 2.5, or 5 mg/mL Serum free cell culture medium

Chromosome aberration assay in accordance with OECD TG 487 with and without metabolic activation. Negative control: solvent (serum free cell culture medium); Positive control: CPA, MMC, colchicine

Human peripheral lymphocytes

Not genotoxic or cytotoxic 6

Ascophyllum Nodosum Extract (4.7%) in water

Not specified 4.7% Ascophyllum Nodosum Extract

An Ames test was performed using a trade name mixture containing 4.7% Ascophyllum nodosum extract in 94.5% water. The procedure was done in accordance to OECD TG 471.

Not specified Not mutagenic or pro-mutagenic activity 70

Cystoseira Compressa Extract

n-Hexane, chloroform, and methanol

1, 2.5, or 5 mg/plate Ames Assay with and without metabolic activation. Negative control: DMSO. Positive controls: BaP, 2-nitrofluorene, and sodium azide.

S. typhimurium (strains TA 98 and TA 100)

Not mutagenic 62

Ecklonia Cava Extract

Enzymatic extraction 911 - 3500 µg/plate; distilled water

Ames assay, with and without metabolic activation. OECD TG 471

S. typhimurium (strains TA 98, TA 100, TA 1535, and TA 1537) and E. coli (WP2uvrA)

Not genotoxic 92


Alcohol Up to 5000 µg/plate; vehicle not specified

Ames assay, with and without metabolic activation

S. typhimurium (strains TA 98, TA 100, TA 1535, and TA 1537) and E. coli (WP2uvrA(pKM101))

Not genotoxic or cytotoxic 9


Alcohol Up to 290 µg/mL Chromosome aberration test, with and without metabolic activation

CHL cells Not genotoxic 9


Enzymatic extraction 87.5 – 350 µg/plate; distilled water

Chromosome aberration test, with and without metabolic activation. OECD TG 473

CHL cells Not genotoxic 92

Fucus Spiralis Extract (12%), tetraselmis chui extract (8%), water (80%)

Not specified 0.06 – 5 µL/plate Ames assay, OECD TG 471; with and without metabolic activation

Not specified. Non-mutagenic; Non-promutagenic 99

Fucus Vesiculosus Extract

Aqueous 0, 0.25, 0.5, or 1 mg/mL; cell medium

Chromosome aberration assay OECD TG 487

Human peripheral lymphocytes

Frequency of chromosome aberrations, mitotic index and extent of DNA damage in cells treated with extract were similar to controls at all concentrations.

100

Fucus Vesiculosus Extract

Aqueous 0, 0.25, 0.5, or 1 mg/mL; cell medium

Comet assay Human peripheral lymphocytes

Extent of DNA damage in cells treated with extract was similar to controls at all concentrations.

100

Halidrys Siliquosa Extract (48%) in water (52%)

Water 0.06 µL – 5 µL/plate Ames assay; OECD TG 471; with and without metabolic activation

S. typhimurium (strains TA 98, TA 100, TA 102, TA 1535)

Non-mutagenic; Non-promutagenic 65





Laminaria digitata Not specified Not specified Ames assay, with and without metabolic activation

S. typhimurium No evidence of mutagenicity 101

Laminaria Saccharina Extract

NR 50, 150, 500, 1500 and 5000 µg/plate; sea water and methylpropandiol

Ames test with and without metabolic activation

S. typhimurium (TA 1535, TA 1537, TA 102, TA98, and TA 100)

Non-mutagenic 102

Macrocystis Pyrifera (Kelp) Extract

Water 1 mL extract in 10 mL 0.9% sodium chloride (concentration of extract was approximately 4%)

Ames test with and without metabolic activation

S. typhimurium (TA 98, TA 100, TA 1535, TA 1537, TA1538)

Non-mutagenic 103

Trade name mixture containing 24% Undaria Pinnatifida Cell Culture Extract

Aqueous 1.5, 5, 15, 50, 150, 500, 1500, and 5000 µg/plate

Bacterial reverse mutation assay performed with and without metabolic activation; OECD TG 471

S. typhimurium (strains TA 98, TA 100, TA 1537, TA 1535) and tryptophan-dependent E. coli (strain WPRuvrA)

Non-mutagenic 104

Cystoseira Amentacea/ Caespitosa/ Brachycarpa Extract (48%), Water (52%)

Water 0.01, 0.1, 1, and 10% A chemiluminescent 3D Assay was performed by using plasmid DNA adsorbed on sensitized microplates as the substrate

NR No direct genotoxicity. 105

In Vivo Ecklonia Cava Extract

Alcohol 0 or 2000 mg/kg Micronucleus assay. Test substance administered via oral gavage. Bone marrow (2,000 erythrocytes) was checked for frequency of micronuclei, after 24, 48, and 72 h.

Male Crlj:CD1(ICR) mice (n = 3)

There was no increase in frequency of micronuclei in any of the time points.

9


Alcohol 0, 500, 1000, or 2000 mg/kg

Micronucleus assay. Test substance administered via oral gavage. Bone marrow (2,000 erythrocytes) was checked for the frequency of micronuclei, after 24 h.

Male Crlj:CD1(ICR) mice (n = 5)

There was no increase in frequency of micronuclei polychromatic erythrocytes (PCE)/(PCE + normochromatic erythrocytes (NCE)) ratio was not significantly different between treatment groups and control groups. No evidence of genotoxicity.

9


Enzymatic extraction 1000, 2000, or 3000 mg/kg; distilled water

Mouse micronucleus assay. The number of mice used in the study was not provided. Administered by gavage. Saline and MMC were the controls. OECD TG 474

Male ICR mice There were no mortalities or abnormal clinical signs in any group. There were no increases in structural or numerical chromosomal aberrations at any dose compared to the negative control.

92

BaP = benzo(a)pyrene; CHL = Chinese hamster lung; CHO = Chinese hamster ovary; CPA = cyclophosphamide; HCl = hydrochloric acid; MMC = mitomycin C; MNPCE = micronucleated polychromatic erythrocyte; NCE = normochromatic erythrocyte; NR = Not Reported; PBS = phosphate-buffered saline; PCE = polychromatic erythrocytes


Table 30. Tumor promotion studies

Test Article Extraction/solvent/ method

Dose/Exposure Route Species (n) Tumor Type Carcinogenicity Model Results Reference

Dermal Undaria Pinnatifida Extract

Dichloromethane extract

1 mg Female ICR mice (n not specified)

Skin - Initiation: a single dermal dose of DMBA (50 µg) - 1 week later, mice were dermally treated twice per week with TPA (1 µg) or Undaria Pinnatifida Extract (1 mg) 1 h prior to treatment with TPA for 15 weeks

TPA: tumors > 1 mm were observed after week 8; average number of tumors was 3.7. Undaria Pinnatifida Extract and TPA: mice did not show 1-mm tumors until week 14 (< 5%); average number of tumors was 0.2.

106

Oral Hizikia Fusiforme Extract

95% Ethanol aq. 0, 2%, or 6% in feed

Male F344 rats (10, control, 8)

Colorectal - Group 1 – standard diet - Group 2 – injected with AOM (15 mg/1 mL/kg once a week for 2 weeks) and standard diet - Group 3 – Injected with AOM and diet with 2% Hizikia Fusiforme Extract - Group 4 – Injected with AOM and diet with 6% Hizikia Fusiforme Extract - After 8 weeks, the rats were killed and necropsied.

- Body weights were similar among groups at 11 weeks. - No tumors were found in the negative control group and 58 tumors were found in the positive control group. Treatment groups had reduced number of tumors (21 each). - Immuno-histochemistry analysis of PCNA expression, a marker of tumor cell proliferation and apoptosis, was lower in treatment groups than in treated control group.

107

Saccharina Angustata Extract (inference from Saccharina angustata powder)

Dried and milled 0 or 5% in feed Female Sprague-Dawley rats (54)

Mammary - After 50 days on respective diets, 4 rats in each group were killed and examined for abnormalities. None were found. - At 55 days treatment groups were administered DMBA by gavage after fasting. - Rats were palpated weekly for tumors. - The rats were killed at 181 - 188 days after DMBA administration and necropsied.

- Weight gains were similar among groups. - First tumors in the control group appeared at 11.0 weeks and 19.8 in the treatment group. - 41 of 54 rats (76%) in control group and 34 of 54 rats (63%) in the treatment group had 1 or more adenocarcinomas at necropsy. - During treatment, 13 rats (8 control and 5 experimental) were euthanized between 74 and 170 days post- DMBA. 10 of these rats had developed large (~ 4 cm in diameter) mammary tumors, 2 developed malignant lymphomas, and 1 developed a large necrotic ear gland tumor (Zymbal's gland carcinoma). There were no other deaths. - 12 tumor-free rats (6 from each group) were found to have small nonpalpable mammary masses; 11 of these were found to be adenocarcinomas and 1 to be an adenoma. 93% of all tumors found in the mammary gland region at necropsywere adenocarcinomas; 5 tumors, which were mostly fibroadenoma but which had focal proliferations of malignant epithelial cells. Other tumors consisted of 7 fibroadenomas, 5 adenomas, 3 epidermal inclusion cysts, and 1 adenocarcinoma of sebaceous glands.

108


Table 30. Tumor promotion studies

Test Article Extraction/solvent/ method

Dose/Exposure Route Species (n) Tumor Type Carcinogenicity Model Results Reference

Sargassum Pallidum Extract

Aqueous. Boiled under reflux and filtered.

400, 600 or 800 mg/kg/d

Male Wistar rats (10)

Gastric - Group 1 – distilled water - Group 2 – 800 mg/kg/d Sargassum Pallidum Extract - Group 3 - 6 – MNNG (25 mg/mL) in drinking for 25 weeks; then 0, 400, 600, or 800 mg/kg Sargassum Pallidum Extract for 8 weeks - All rats were killed at 33 weeks, blood analyzed, and stomachs examined.

- There were no mortalities. - Compared to group 1 (control), Sargassum Pallidum Extract increased serum IL-2, IL-4, and IL-10 levels in group 2; serum IL-2, IL-4, and IL-10 levels in group 3 were decreased. - Compared to group 1, Sargassum Pallidum Extract decreased serum IL-6, IL-1β, and TNF-α levels in group 2; serum IL-6, IL-1β, and TNF-α levels in group 3 were increased. - Compared with group 3, Sargassum Pallidum Extract dose-dependently decreased serum IL-6, IL-1β, and TNF-α levels in groups 4, 5, and 6. - Concentration of serum and gastric mucosa MDA decreased in a dose-dependent manner in groups 4, 5, and 6. - Concentration of serum and gastric mucosa GSH and antioxidant enzyme activities increased in a dose-dependent manner in groups 4, 5, and 6. - Sargassum Pallidum Extract could decrease inflammatory response and improve immunity function partly through stimulating inflammatory cytokines (IL-2, IL-4, IL-10) production and inhibiting pro-inflammatory cytokines production.

109

Undaria Pinnatifida Powder

Not specified 0, 1.0% or 5.0% in feed


Mammary - Initiation: a single dose of DMBA (20 mg) by gastric intubation - Once tumors reached 1 cm, rats were divided between 3 treatment groups for 8 weeks - Rats were then killed and all mammary tumors were histologically examined and thyroid glands, ovaries, and adrenal glands were weighed. Blood samples collected for measurement of serum total iodine concentration and serum T4 levels.

No differences in body weight gains between groups. Tumors in control group increased by more than 450%; tumor growth was suppressed in the 1% group and there was almost no change in tumor size in the 5% group. Mean combined weight of all mammary tumors of each rat in treatment groups was lower than that in the control group (~ 7 vs 20 g) at end of experiment. Weights of thyroid glands, ovaries, and adrenal glands did not differ among groups. Concentration of serum iodine was greater in treatment groups compared to controls. Serum iodine concentration had a positive relationship with concentration of Undaria Pinnatifida Powder in diet. Serum T4 levels showed no differences among groups. Test substance did not promote mammary tumors and suppressed tumor growth after a single dose of DMBA.

98

Undaria Pinnatifida Extract

Filtered aqueous extract of powdered stems and thick leaves

1.5 g in 1000 mL water


Mammary - Initiation: a single dose of DMBA (20 mg) by gastric intubation - 1 week later, treatment began for 32 weeks - Mammary tumors were removed and measured

- Body weight gains were similar in both groups - Incidence of tumors at end of experiment was 22% vs 100% (controls) - The number of tumors was an average of < 1 vs. ~ 7 (controls) - Total tumor diameters was < 250 vs > 5000 mm - Histologically, mammary tumors were cystic adenocarcinoma, and tumors in treatment group had a decreased density of epithelial cells and fibrosis.

97

AOM = azoxymethane; DMBA = 7,12-dimethylbenz(a)anthracene; GSH = glutathione; MDA = malondialdehyde; MNNG = N-methyl-N′-nitro-N-nitrosoguanidine; PCNA = proliferating cell nuclear antigen; T4 = thyroxin; TPA = 12-O-tetradecanoylphorbol-13-acetate


Table 31. Dermal irritation and sensitization

Ingredient Test Substance Concentration/Dose of the test substance

Test Population Procedure Results Reference

Irritation IN VITRO

Laminaria Japonica, Nereocystis Leutkeana, and Macrocystis Pyrifera Extract

Trade name mixture containing Laminaria Japonica (7%), Nereocystis Leutkeana (7%), Macrocystis Pyrifera Extract (7%), and pentaerythrityl tetraethylhexanoate (79%)

100%; 30 µL (liquid) or 25 mg (solid)

3 Reconstructed human epidermal model; 3 tissues treated with test substance and incubated for 60 minutes

Non-irritating 114

Sargassum Filipendula Extract Trade name mixture containing Sargassum Filipendula Extract (1.3%), water (81.78%), Sorbitol (14%), hypnea musciformis Extract (1.4%), gellidiela acerosa Extract (1.3%), methylparaben (0.2%), propylparaben (0.025%)

100% 3 30 µL (liquid) or 25 mg (solid) of the test substance was applied to 3 tissue inserts and incubated for 60 minutes; inserts were then washed, transferred to fresh media

Non-irritating 115

Undaria Pinnatifida Cell Culture Extract

Trade name mixture containing Undaria Pinnatifida Cell Culture Extract (24%) with water as solvent

30 µL (liquid); 25 mg (solid)

3 per test concentration

The test substance, either liquid or solid, was applied to reconstructed human epidermis and incubated for 60 minutes. These tissue inserts were then washed and cell viability was measured.

Non-irritating 113

Undaria Pinnatifida Extract Trade name mixture containing Undaria Pinnatifida Extract (0.5-2%) in caprylic/capric triglycerides

100%; 10 µL 3 OECD TG 439; 3 replicates of human skin cell models were treated with the test substance for approximately 15 minutes; time of recovery was 42 hours ± 1 hour

Non-irritating 216

ANIMAL Ascophyllum Nodosum Extract Ascophyllum Nodosum extract 0.5 mL (liquid); 0.5 g

(solid) NR Dermal irritation assay performed according to OECD TG

404; application for 4 hours Non-irritating 91

Ascophyllum Nodosum Extract Ascophyllum nodosum extract 0.5 g; concentration not stated

3 male rabbits A dermal irritation assay was performed according to OECD TG 404 guidelines. The test substance was administered in three patches on areas of 12-20 cm2 to the shaved backs of the rabbits under semi-occlusion for 3 min (patch 1), 1 h (patch 2), and 4 h (patch 3). There were no signs of irritation after the removal of patch 1 from one rabbit; patch 2 was then applied to the same rabbit. There were no signs of irritation after patch 2 was removed; patch 3 was then applied to all three rabbits. The test site was examined at 1, 24, 48, and 72 hours after removal of the last patch.

Non-irritating 6

Laminaria Digitata Extract Trade name mixture containing Laminaria Digitata Extract (≤ 10%), artemisia vulgaris extract (≤ 10%), phenoxyethanol (0.8%), and water

20%; 0.5 mL 6 New Zealand White rabbits

The test material was applied to an area of 6 cm2, and covered with an occlusive patch for 24 hours. Animals were examined 24 and 72 hours after administration of test material.

Non-irritating 94

Laminaria Digitata Extract Trade name mixture containing Laminaria Digitata Extract, water, and dipropylene glycol

0.5 g; concentration not stated

Rabbits (# not stated)

Dermal irritation assay; details not available Non-irritating 49





Laminaria Digitata Extract Trade name mixture containing Laminaria Digitata Extract, water, and sea salt

0.5 g; concentration not stated

Rabbits (# not stated)

Dermal irritation assay; details not available Non-irritating 49

HUMAN Alaria Esculenta Extract Trade name mixture containing

Alaria Esculenta Extract (<5%) and in caprylic/capric triglycerides

100%; 20 µL 10 24-hour patch test; occlusive patch; over a surface of 50 mm2 Non-irritating 217

Ascophyllum Nodosum Extract Trade name mixture containing 4.7% Ascophyllum Nodosum Extract in 94.5% water

NR NR A cutaneous irritation test was performed according to OECD TG 439. No additional details were provided.

Non-irritating 70

Ascophyllum Nodosum Extract Trade name mixture containing 0.5 – 10% Ascophyllum Nodosum Extract in water

100% 10 24-hour patch test; occlusive patch Non-irritating 125

Ascophyllum Nodosum Extract and Halopteris Scoparia Extract

Ascophyllum Nodosum Extract (40.5%), Halopteris Scoparia Extract (13.5%), and water

100%; 0.02 mL 11 48-hour patch test; occlusive patch Non-irritating 218

Cystoseira Amentacea/Caespitosa/ Brachycarpa Extract

52% water; 48% Cystoseira Amentacea/Caespitosa/ Brachycarpa Extract

NR 11 0.02 mL of test substance applied to back under an occlusive patch for 48 hours

Non-irritating 105

Cystoseira Baccata Extract Cystoseira Baccata Extract in water (0.5 %)

100% 10 24-hour patch test; occlusive dressing Non-irritating 49

Cystoseira Baccata Extract Cystoseira Baccata Extract in water (0.5 %)


Cystoseira Tamariscifolia Extract

Trade name mixture containing Cystoseira Tamariscifolia Extract (0.5 %) and caprylic/capric triglycerides



Cystoseira Tamariscifolia Extract (0.5 – 10%), glycerin, and water


Dictyopteris Polypodioides Extract

Dictyopteris Polypodioides Extract (0.5 – 10%), water, and glycerin



Dictyopteris Polypodioides Extract (0.5 – 10%) and water



Dictyopteris Polypodioides Extract (0.5 – 10%) and caprylic/capric triglyceride


Fucus Serratus Extract Fucus Serratus Extract (44%) and water (56%)

5%; 0.02 mL 10 48-hour patch test; occlusive dressing Non-irritating 219

Fucus Spiralis Extract Trade name mixture consisting of Fucus Spiralis Extract (1 - 3%) in butylene glycol and water

100%; 20 µL 12 24-hour patch test; occlusive patch; application over an area of 50 mm2

Non-irritating 220

Fucus Spiralis Extract Trade name mixture consisting of Fucus Spiralis Extract (< 5%) in caprylic/capric triglycerides

100%; 20 µL 10 Test substance applied to an area of 50 mm2 under an occlusive patch for 30 minutes and 24 hours

Slightly irritating at the 30 minute reading and non-irritating at the 24 hour reading

116





Fucus Spiralis Extract Fucus Spiralis Extract (12%), tetraselmis chui extract (8%), water (80%)

10%; 0.02 mL 14 48-hour patch test; occlusive dressing Non-irritating 221

Fucus Vesiculosus Extract Fucus Vesiculosus Extract (0.5 – 10%), water, and dipropylene glycol


Fucus Vesiculosus Extract Trade name mixture consisting of Fucus Vesiculosus Extract (5%) and caprylic/capric triglycerides (95%)

100%; 0.02 mL 10 24-hour patch test; occlusive dressing; application over an area of 50 mm2

Non-irritating 116

Halidrys Siliquosa Extract Halidrys Siliquosa Extract (52%) in water (48%)

5%; 0.02 mL 13 Test substance was diluted to 5% and applied to the back under an occlusive patch for 48 hours

Non-irritating 65

Halopteris Scoparia Extract Halopteris Scoparia Extract (0.5 – 10%), water, and dipropylene glycol


Himanthalia Elongata Extract Trade name mixture containing Himanthalia Elongata Extract (0.5 %), water, and dipropylene glycol


Himanthalia Elongata Extract and Undaria Pinnatifida Extract

Himanthalia Elongata Extract (20%), Undaria Pinnatifida Extract (37%), and water (43%)

NR 10 Test substance (0.02 mL) applied to the back under an occlusive patch for 48 hours

Very Slightly Irritating (average irritant score of 0.10)

64

Himanthalia Elongata Extract, Fucus Vesiculosus Extract, saccharomyces cerevisiae extract

Himanthalia Elongata Extract (62%), Fucus Vesiculosus Extract (1.4%), saccharomyces cerevisiae extract (0.1%), and water (36.5%)

10%; 160 µL 10 females Test substance was applied to the back under a semi-occlusive patch for 48 h ± 4 h.

Non-irritating 222

Laminaria Digitata Extract Laminaria Digitata Extract and water

0.5 % 10 24-hour patch test; occlusive patch Non-irritating 49

Laminaria Digitata Extract Trade name mixture containing Laminaria Digitata Extract (<5%) in caprylic/capric triglycerides

100%; 20 µL 12 24-hour patch test; test substance applied to an area of 50 mm2; occlusive patch

Non-irritating 223

Laminaria Digitata Extract Laminaria Digitata Extract (1.5-2.5%) in water and propylene glycol

100%; 20 µL 12 Test substance applied under an occlusive patch for 30 minutes or 24 hours over an area of 50 mm2

Moderately irritating at the 30 minute reading; Slightly irritating at the 24 hour reading

117

Laminaria Hyperborea Extract Trade name mixture containing Laminaria Hyperborea Extract (1-3%) in water

100%; 20 µL 10 24-hour patch test; occlusive patch Non-irritating 224

Laminaria Japonica Extract Skin cream containing a 50/50 aqueous propylene glycol extract of Laminaria japonica

10%; 20 mg 25 Patches were applied to the forearms of subjects using Finn chambers for up to 48 h and scored for irritation 6 h after patch removal.

Non-irritating 51

Laminaria Ochroleuca Extract Trade name mixture consisting of Laminaria Ochroleuca Extract (<5%) in caprylic/capric triglycerides

2%; 20 µL 11 Single 24 hour application over an area of 50 mm2; occlusive patch

Non-irritating 225





Laminaria Ochroleuca Extract Cosmetic product containing Laminaria Ochroleuca Extract (5%), caprylic/capric triglyceride (94.75%), and tocopherols (0.25%)

10%; 0.02 mL 10 48-hour occlusive single patch test Non-irritating 226

Lessonia Nigrescens Extract Lessonia Nigrescens Extract (12%), water (44%), butylene glycol (44%)

5%; 0.02 mL 10 48-hour occlusive single patch test Non-irritating 227

Laminaria Saccharina Extract Trade name mixture containing Laminaria Saccharina Extract (1 -3%) in water and propylene glycol

8, 16, or 100%; 20 µL 10 Six occlusive patches (drenched with test substance) per concentration were applied to the arms over a 50 mm2 surface for 24 and 48 hours

100% dose was slightly irritating; minimal erythema in 5/10 subjects; 16% dose was non-irritating; 8% dose was non-irritating

118


Macrocystis Pyrifera (Kelp) Extract (water extract)

4% 10 48-hour occlusive single patch test Non-irritating 103

Pelvetia Canaliculata Extract Trade name mixture containing Pelvetia Canaliculata Extract (1 -3%) in butylene glycol and water

100%; 20 µL 12 Test substance was applied to skin under occlusive patches over a 50 mm2 surface for 30 minutes and 24 hours

Non-irritating at the 30 minute reading; Slightly irritating at the 24 hour reading

228

Pelvetia Canaliculata Extract Trade name mixture containing Pelvetia Canaliculata Extract (1 -3%) in propylene glycol and water

100: 20 µL 12 Test substance was applied to skin under occlusive patches over a 50 mm2 surface for 30 minutes and 24 hours

Moderately irritating at the 30 minute reading; slightly irritating at the 24 hour reading

119

Pelvetia Canaliculata Extract Trade name mixture containing Pelvetia Canaliculata Extract (0.5 - 3%) in water

100%; 20 µL 11 24-hour patch test; occlusive patch Non-irritating 136

Pelvetia Canaliculata Extract Pelvetia Canaliculata Extract (44%) and water (56%)

100%; 0.02 mL 11 48-hour patch test; occlusive patch Non-irritating 229

Pelvetia Canaliculata Extract and Laminaria Digitata Extract

Trade name mixture containing Pelvetia Canaliculata Extract and Laminaria Digitata Extract extracted in propylene glycol with panthenol (the amount of dry extract of both extracts combined is estimated to be 5.5-9.0%)

5, 10, and 100%; 20 µL 10 Test substance was applied to skin under occlusive patches over a 50 mm2 surface for 24 and 48 hours

Mild irritation at the 100% concentration; Minimal irritation at the 10% concentration; No irritation at the 5% concentration

121

Phyllacantha Fibrosa Extract Phyllacantha Fibrosa Extract (0.5 – 10%) in water


Sargassum Glaucescens Extract Trade name mixture containing 20% Sargassum Glaucescens Extract, 79% water, and 1% phenoxyethanol

10% 10 Test substance was applied under an occlusive patch for 48 hours

Non-irritating 166

Sargassum Muticum Extract Sargassum Muticum Extract (46%) and water (54%)

100%; 0.02 mL 11 Test substance was applied under an occlusive patch for 48 hours

Non-irritating 230

Sphacelaria Scoparia Extract Sphacelaria Scoparia Extract (0.5 %), water, and dipropylene glycol

100%; 15 mL 11 24-hour patch test; occlusive dressing Non-irritating 49





Undaria Pinnatifida Extract Trade name mixture containing Undaria Pinnatifida Extract (< 5%) in water and propylene glycol

100%; 20 µL 12 Test substance applied to the skin over an area of 50 mm2 for either 30 minutes or 24 hours; occlusive patch

Moderately irritating after 30 minutes; Mildly irritating after 24 hours

120

Undaria Pinnatifida Extract Trade name mixture containing Undaria Pinnatifida Extract (0.5%) in water and dipropylene glycol

NR 10 24-hour patch test; occlusive dressing Non-irritating 49

Undaria Pinnatifida Extract Undaria Pinnatifida Extract (0.5 – 10%) and caprylic/capric triglyceride


Sensitization

IN VITRO Sargassum Filipendula

Extract Trade name mixture

containing Sargassum Filipendula Extract (1.3%),

water (81.78%), sorbitol (14%), hypnea musciformis

extract (1.4%), gellidiela acerosa extract (1.3%), methylparaben (0.2%),

propylparaben (0.025%)

0.98-2000 µM 2 per test concentration

ARE-Nrf2 Luciferase Test performed according to

OECD TG 442D; immortalized adherent human keratinocyte cell line; 12 test concentrations ranging from 0.98 to 2000 µM were used

Non-sensitizing

231


Trade name mixture containing Undaria

Pinnatifida Cell Culture Extract (24%) with water as

solvent

0.98 – 2000 µM 3 per test concentration ARE-Nrf2 Luciferase Test performed according to

OECD TG 442D; immortalized adherent human keratinocyte cell line; 12 test concentrations ranging from 0.98 to 2000 µM were used

Non-sensitizing 122


Undaria Pinnatifida Cell Culture Extract (24%) with

water as solvent in acetonitrile

5 mM or 25 mM 3 per test concentration Direct Peptide Reactivity Assay (DPRA) performed according to OECD TG

442C; 1:10 ratio of Cysteine Peptide (0.5 mM) and test

chemical (5 mM)) and 1:50 ratio of Lysine peptide (0.5 mM) and test chemical (25

mM)

Non-sensitizing 123

ANIMAL Ascophyllum Nodosum Extract Ascophyllum Nodosum Extract 0.1 to 400 µL of 25% to

75% water solutions 20 test and 10 control guinea pigs

Magnusson and Kligman (guinea pig maximization test); OECD TG 406

Non-sensitizing 91

Cystoseira Amentacea/ Caespitosa/Brachycarpa Extract

Cream containing 0.0023% Cystoseira Amentacea/ Caespitosa/Brachycarpa Extract

100% 25 Maximization study. Product was applied under a semi-occlusive patch. No other details regarding this study were provided.

Non-sensitizing 124





HUMAN Alaria Esculenta Extract Trade name mixture consisting

of Alaria Esculenta Extract (<5%) in caprylic/capric triglycerides – dried before extraction

100%; 25 µL 50 The sensitizing potential of the test substance was studied using a HRIPT. The test material was applied to the upper back under a patch. Occlusive conditions. During the induction phase, patches are applied 3 times per week for 3 weeks, for a total of 9 applications. If the test substance caused a moderate reaction (2-level), the application is moved to an adjacent area. If 3-level or 4-level reactions were noted, applications are discontinued. Two weeks after the final induction application, a challenge patch is applied to a previously untested site adjacent to the original patch site. Patches were removed and sites were scored 24 and 72 hours after application.

Non-irritating; Non-sensitizing

126

Alaria Esculenta Extract Night cream containing 0.05% Alaria Esculenta Extract

0.2 g 105 A HRIPT was performed. Semi-occlusive conditions. The test material was applied to the 1 in2 absorbent pad portion of a clear adhesive dressing.

Non-sensitizing 232

Alaria Esculenta Extract Trade name mixture consisting of Alaria Esculenta Extract (0.5-2.5%) in butylene glycol and water

100%; 25 µL 50 The test substance was applied (under an occlusive patch) 3 times a week during the induction phase and once a week during challenge phase. The induction phase lasts for 3 weeks, followed by a latent phase which lasts for 2 weeks.


127

Ascophyllum Nodosum Extract Ascophyllum Nodosum Extract (0.5 – 10%)

100%; 25 µL 50 A HRIPT was performed. Occlusive conditions. Non-irritating; Non-sensitizing

125,233

Cystoseira Baccata Extract Cystoseira Baccata Extract (0.5 – 10%) in water

100%; 25 mL 50 A HRIPT was performed. Occlusive conditions. Non-irritating; Non-sensitizing

49,233


Cystoseira Tamariscifolia Extract (0.5 – 10%), glycerin, and water

20%; 25µL 105 A HRIPT was performed. Occlusive conditions. Non-irritating; Non-sensitizing

125,233


Dictyopteris Polypodioides Extract (0.5 – 10%), water, and glycerin

100% 50 Repeated epicutaneous applications. Occlusive conditions. Non-irritating; Non-sensitizing

125


Dictyopteris Polypodioides Extract (0.5 – 10%) and water

100%; 25 µL 50 Repeated epicutaneous applications. Occlusive conditions. Non-irritating; Non-sensitizing

125,233


Dictyopteris Polypodioides Extract (0.5 – 10%) , caprylic/capric triglyceride

100%; 25µL 50 A HRIPT was performed. Occlusive conditions. Non-irritating; Non-sensitizing

125,233

Fucus Spiralis Extract Trade name mixture consisting of Fucus Spiralis Extract (1-3%) in butylene glycol and water

100%; 200 µL 50 A HRIPT was performed. Occlusive conditions Non-sensitizing 130

Fucus Spiralis Extract Fucus Spiralis Extract (12%), tetraselmis chui extract (8%), and water (8%)

100% 105 A HRIPT was performed. No dosing details were provided. Non-sensitizing 131

Fucus Vesiculosus Extract Trade name mixture containing Fucus Vesiculosus Extract (0.1%)

10%; 0.2 mL 58 A HRIPT was performed. Semi-occlusive conditions. Non-sensitizing 133

Fucus Vesiculosus Extract Trade name mixture containing Fucus Vesiculosus Extract (0.1%)

100%; 0.2 mL 56 A HRIPT was performed. Semi-occlusive conditions. Non-sensitizing 132

Fucus Vesiculosus Extract Trade name mixture consisting of Fucus Vesiculosus Extract (5%) and caprylic/capric triglycerides (95%)

100%; 200 µL 52 A HRIPT was performed. Occlusive conditions. Non-sensitizing 116





Halidrys Siliquosa Extract Halidrys Siliquosa Extract (48%) and water (52%)

100% 107 A HRIPT was performed. Occlusive conditions. Non-sensitizing 65

Halopteris Scoparia Extract Halopteris Scoparia Extract (0.5 – 10%), water, dipropylene glycol

100%; 15 µL 50 Repeated epicutaneous applications. Occlusive conditions. 40 day test period.

Non-sensitizing 125,233

Himanthalia Elongata Extract Cream containing 0.2% Himanthalia Elongata Extract

100% 102 A HRIPT was performed. Occlusive conditions. Non-irritating; Non-sensitizing

124

Laminaria Digitata Extract Laminaria Digitata Extract (<5%) in caprylic/capric triglycerides

100%; 20 µL 46 A HRIPT was performed. Occlusive conditions. Non-sensitizing 134

Laminaria Digitata Extract Trade name mixture containing Laminaria Digitata Extract (8-12%), urea (12-18%), synthetic glucosamine HCl (10-15%), saccharomyces cerevisiae extract (8-12%), and phenoxyethanol (0.8%)

10%; 0.2 mL (liquid) or 0.2 g (solid)

100 A HRIPT was performed. Occlusive conditions. Non-irritating; Non-sensitizing

135

Laminaria Digitata Extract Trade name mixture containing Laminaria Digitata Extract (≤ 10%), artemisia vulgaris extract (≤ 10%), phenoxyethanol (0.8%), and water


100 A HRIPT was performed. Occlusive conditions/ Non-irritating; Non-sensitizing

94

Laminaria Saccharina Extract Trade name mixture containing Laminaria Saccharina Extract (1-3%) in water and propylene glycol

20%; 25 µL 50 The test substance was applied (under an occlusive patch) 3 times a week during the induction phase and once a week during challenge phase. The induction phase lasts for 3 weeks, followed by a latent phase which lasts for 2 weeks.


129


Macrocystis Pyrifera (Kelp) Extract (water extract)


103

Pelvetia Canaliculata Extract Trade name mixture containing Pelvetia Canaliculata Extract (0.5-3%) in water


136

Pelvetia Canaliculata Extract Pelvetia Canaliculata Extract (44%) and water (56%)

100% 111 A HRIPT was performed. Occlusive conditions. Non-sensitizing 137

Phyllacantha Fibrosa Extract Phyllacantha Fibrosa Extract (0.5 – 10%) in water

100%; 25 µL 50 Repeated cutaneous applications. Occlusive conditions. Non-sensitizing 125,233

Sargassum Filipendula Extract Face cream containing 1.2% Sargassum Filipendula Extract

0.2 g 206 A HRIPT was performed. A 4 cm2 occlusive patch was used. Non-sensitizing 138

Sargassum Muticum Extract Eye cream containing 0.076% Sargassum Muticum Extract

0.2 g 103 A HRIPT was performed. The test material was applied to the 1 inch2 absorbent pad portion of a clear adhesive dressing.

Non-sensitizing 139

Sargassum Muticum Extract Skin care product containing 0.076% Sargassum Muticum Extract

0.2 g 104 A HRIPT was performed. The test material was applied to the 1 inch2 absorbent pad portion of a clear adhesive dressing.

Non-sensitizing 140

Sphacelaria Scoparia Extract Sphacelaria Scoparia Extract, water, and dipropylene glycol (test concentration unknown)

100% 50 Repeated epicutaneous applications. Occlusive conditions. Hypoallergenic 49

Undaria Pinnatifida Extract Trade name mixture containing Undaria Pinnatifida Extract (<5%) in caprylic/capric triglycerides


141

Undaria Pinnatifida Extract Undaria Pinnatifida Extract in caprylic/capric triglycerides


125





Undaria Pinnatifida Extract Undaria Pinnatifida Extract (0.5 – 10%) in glycerin and water


125

ARE = Antioxidant Response Elements; HRIPT = Human Repeat Insult Patch Test; Nrf2 = Nuclear factor-erythroid 2-related factor; NR = Not Reported Table 32. Ocular Irritation Studies Test Article Concentration/Dose Test Population Procedure Results Reference

IN VITRO Trade name mixture containing Ascophyllum Nodosum Extract (4.7%) in water (94.5%)

NR NR HET-CAM test Non-irritating 70

Ascophyllum Nodosum Extract (40.5%), Halopteris Scoparia Extract (13.5%), and water

100% NR HET-CAM test; incubation for 11 days Non-irritating 234

Cystoseira Amentacea/Caespitosa/Brachycarpa Extract (48%), water (52%)

100% NR HET-CAM test; incubation for 11 days Slightly irritating 105

Fucus Serratus Extract (44%) and water (56%)


Halidrys Siliquosa Extract (48%) in water (52%)


Himanthalia Elongata Extract (20%), Undaria Pinnatifida Extract (37%), water (43%)

10% NR HET-CAM test Slightly irritating 64

Himanthalia Elongata Extract (62%), Fucus Vesiculosus Extract (1.4%), saccharomyces cerevisiae extract (0.1%), water (36.5%)

10% 4 HET-CAM test Slightly irritating 236

Trade name mixture containing Laminaria Digitata Extract (8-12%), urea (12-18%), synthetic glucosamine HCl (10-15%), saccharomyces cerevisiae extract (8-12%), and phenoxyethanol (0.8%)


4 HET-CAM test; incubation for 10 days Non-irritating 237

Laminaria Japonica Extract (7%), Nereocystis Leutkeana Extract (7%), Macrocystis Pyrifera Extract (7%), and pentaerythrityl tetraethylhexanoate

50 µL (liquid) or 50 mg (solid)

NR Test substance was applied to reconstructed cornea epithelium; after application, epithelia was incubated for 30 (liquid) or 90 (solid) minutes

Non-irritating 114

Laminaria Ochroleuca Extract (5%), caprylic/capric triglyceride (94.75%), tocopherols (0.25%)

10% NR HET-CAM test Moderately irritating 142

Lessonia Nigrescens Extract (12%), water (44%), butylene glycol (44%)

10% NR HET-CAM test Non-irritating 238

Macrocystis Pyrifera (Kelp) Extract 4% NR HET-CAM test Mildly irritating 103


Table 32. Ocular Irritation Studies Test Article Concentration/Dose Test Population Procedure Results Reference Trade name mixture containing Sargassum Filipendula Extract (1.3%), water (81.78%), sorbitol (14%), hypnea musciformis extract (1.4%), gellidiela acerosa extract (1.3%), methylparaben (0.2%), propylparaben (0.025%)

100%, 50 µL (liquid) or 50 mg (solid)

2 Test substance was applied to reconstructed cornea epithelium and allowed to incubate for 90 minutes

Non-irritating 115

Sargassum Muticum Extract (46%) and water (54%)

100% NR HET-CAM test; incubation for 11 days Slightly-irritating 239

Undaria Pinatifida Cell Culture Extract (24%) in water

50 µL (liquid) or 50 mg (solid)

NR Test substance was applied to reconstructed cornea epithelium; after application, epithelia was incubated for 30 (liquid) or 90 (solid) minutes

Non-irritating 113

ANIMAL Ascophyllum Nodosum Extract 100 mg 3 OECD TG 405; New Zealand White rabbits;

test substance was instilled into one eye of each rabbit and rinsed after 1 hour; examination occurred 1, 24, 48, and 72 hours, and 7 days after administration

The maximum irritation score was 6.7 out of 8 at 1 h post-instillation; the score decreased to 0 by day 7, which indicated that the induced changes were reversible, and thus, the effects of the test substance were classified as ‘irritation’ and not as ‘corrosion.’ The test substance was rated as a mild ocular irritant.

6

Ascophyllum Nodosum Extract NR NR OECD TG 405; no other details were provided for this study

Slightly irritating 91

Trade name mixture containing Laminaria Digitata Extract (≤ 10%), artemisia vulgaris extract (≤ 10%), phenoxyethanol (0.8%), and water

20%; 0.1 mL 6 The test material was placed on the everted lower lid of one eye of each New Zealand White rabbit. The upper and lower lids were then gently held together for one second before releasing. Lesions were evaluated at 24 and 72 hours post instillation.

Non-irritating 94

HUMAN Eye cream containing 0.076% Sargassum Muticum Extract

100% 31 Test substance was applied to the eye contour of 31 subjects. Half of the subjects were soft-contact lens wearers. Exam was performed 4 weeks after usage.

Non-irritating 144

NR = Not Reported Table 33. Case Reports of brown algae Ingredient/substance (dose, if known) Details Reference Fucus vesiculosus supplement (1200 mg 3 times per day)

18-year-old female presented with polyuria, polydipsia, extreme faintness, and a general poor condition. She had been on a hypocaloric diet for 3 months and taking Fucus vesiculosus supplements. Renal biopsy showed widespread tubular degeneration, and diffuse lymphomonocytic infiltrate; the glomeruli displayed scarce and focal mesangial proliferation, but the basal membrane appeared intact. The supplement was tested for heavy metals: arsenic, 21.3 mg/kg; cadmium, 0.3 ppm; mercury, 0.06 ppm; and chrome, 4 ppm. The patient recovered within 1 year.

240

Kelp tablets 54-year-old female developed thrombocytopenia with mucocutaneous bleeding after ingesting kelp tablets (that contained 1.3 µg/g arsenic) twice daily for 6 weeks. Marrow aspirate demonstrated normal megakaryocytes and dyserythropoiesis. After discontinuation of the supplements and treatment with steroids and azathioprine, her platelet count recovered after 3 months.

145

Kelp supplements A 54-year-old woman presented with a 2-year history of worsening alopecia and memory loss. She also had a rash, increasing fatigue, nausea, and vomiting to the point of disablement. She took daily kelp supplements. A urine sample showed an arsenic level of 83.6 μg/g creatinine (normal < 50 μg/g creatinine). A sample from her kelp supplements contained 8.5 mg/kg arsenic. Within weeks of discontinuing the supplements, her symptoms resolved and arsenic blood and urine levels were undetectable.

146


Table 34. Oral clinical trials

Test Article

Extraction/ Solvent Method or Characterization Study group Study Details Results Reference

Ascophyllum Nodosum Powder (0.5 g/d)

Powdered plant Healthy female subjects (n = 42)

After a 4-day period of keeping a food diary, subjects were administered capsules containing extract or potassium iodide daily for 14 days, then repeated 4-day food diary. All-day urine sample was collected on fourth day of run-in period and last day of treatment period (day 19) and fasted blood samples were collected on fourth day of run-in period and on day after treatment period (day 20).

There was an increase in urinary iodine concentrations (median 140 mg/l vs78 mg/l) in the treatment group. TSH increased slightly but within normal range 2 subjects. Increase in TSH concentrations may be associated with iodine-induced hypothyroidism, especially in those subjects with low iodine stores, although no change in the concentrations of thyroid hormones was observed. There were no adverse events reported during this experiment.

147

Ecklonia Cava Extract (400 mg/d)

Alcohol Subjects with hyper-cholesterolaemia (n = 52)

Uncontrolled, open-label, single-arm study for 12 weeks

Hematological, clinical chemistry, and urinalysis did not reveal any adverse effects. There was one instance (2.2%) each of nausea, dyspepsia, diarrhea, and alopecia reported.

9,148

Ecklonia Cava Extract (0, 72, or 144 mg/d)

Phlorotannin-rich Overweight subjects (n = 32 or 33)

Randomized, double-blind, three-arm, parallel trial for 12 weeks

Hematological and clinical chemistry did not reveal any adverse effects. Only high-dose group showed significant decreases in serum glucose and systolic blood pressure. No adverse signs were observed during the trial.

9

Ecklonia Cava Extract (0 or 400 mg/d)

Alcohol Overweight subjects (n = 40)

Randomized, double-blind, and placebo-controlled trial for 12 weeks. Administered as 200 mg twice per day in capsules

There were no adverse events reported that were related to the test substance.

24

Undaria Pinnatifida Powder (desalinated; 5040 mg/d)

Powdered Hypertensive subjects (n = 18)

Subjects were gender and age matched to control group. Capsules (420 mg/capsule; 4 capsules/dose) 3 times/d with meals. Examined for body weight, BP, and blood chemistry parameters prior to experiment, at 4 weeks, and at 8 weeks. 1 subject in treatment group left study for personal reasons, so final number of paired subjects was 18, (some of her data (e.g., adverse effects) were used).

Compliance was not consistent; 6 subjects followed protocol; 1 ingested 9 capsules/d, 2 ingested 8 capsules/d, 6 ingested 6 capsules/d, and 3 ingested 3capsules/d. Average intake was estimated to be 7.9 capsules or 3.3 g/d. Average SBP in treatment group decreased by 13 mmHg from the baseline after 4 weeks, and was reduced by 8 mmHg below baseline after 8 weeks. Average DBP decreased by 9 mmHg from baseline after 4 weeks and by 8 mmHg after 8 weeks. There were no significant changes in either SBP or DBP in control group. However, the differences in reductions in SBP and DBP were significant between the treatment group and control group. Hypercholesterolemia subjects in treatment group had decreased total cholesterol by 8% after 4 weeks; no changes were observed in subjects with normal cholesterol levels. Adverse effects included 2 cases of indigestion and 1 case of diarrhea, all of which resolved quickly without treatment.

67

BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure; TSH = thyroid-stimulating hormone Table 35. Change in menstrual cycle with the oral administration of Fucus Vesiculosus Powder149

Subject Menstrual cycle length Days of Menstruation

Baseline Low-Dose High-Dose Baseline Low-Dose High-Dose 1 16.3 ± 0.6 days 26.0 ± 1.4 days 31.2 ± 1.1 days 9.3 ± 0.6 days 6.3 ± 1.8 days 4.5 ± 0.7 days 2 23.0 ± 1.7 days 28.5 ± 0.7 days - 8.0 ± 1.0 days 5.3 ± 2.5 days - 3 27.3 ± 0.6 days 31.5 ± 0.7 days 36.0 ± 2.8 days 6.3 ± 1.5 days 5.8 ± 0.4 days 3.5 ± 0.7 days - = no data


REFERENCES

1. Nikitakis J and Kowcz A. Web-based International Cosmetic Ingredient Dictionary and Handbook (wINCI Dictionary). http://webdictionary.personalcarecouncil.org/jsp/Home.jsp. Last Updated 2018. Date Accessed 7-23-2018.

2. Dayton P. Ecology of kelp communities. Annual Review of Ecology and Systematics. 1985;16:215-245. https://www.annualreviews.org/doi/abs/10.1146/annurev.es.16.110185.001243?journalCode=ecolsys.1.

3. Becker LC, Bergfeld WF, Belsito DV, et al. Safety assessment of phytosterols as used in cosmetics. Washington, DC: Cosmetic Ingredient Review (CIR). 2014. http://online.personalcarecouncil.org/ctfa-static/online/lists/cir-pdfs/FR651.pdf. Date Accessed 7-23-2018.pp. 1-23.

4. Johnson Jr WJ, Heldreth B, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks Jr JG, Shank RC, Slaga TJ, Snyder PW, and Gill LJ. Safety assessment of polysaccharide gums as used in cosmetics. 2015. pp.1-87. Washington, DC: Cosmetic Ingredient Review (CIR).Available from CIR (https://www.cir-safety.org/ingredients). Date Accessed 7-23-2018

5. European Chemicals Agency (ECHA). Ascophyllum nodosum, extract; EC number: 700-983-2. http://echa.europa.eu/registration-dossier/-/registered-dossier/7294. Last Updated 2017. Date Accessed 7-23-2018.

6. European Chemicals Agency (ECHA). Ascophyllum nodosum, ext. EC number: 283-907-6, CAS number: 84775-78-0. http://echa.europa.eu/registration-dossier/-/registered-dossier/14266. Last Updated 2017. Date Accessed 7-23-2018.

7. European Medicines Agency (EMA). Assessment report on Fucus vesiculosus L., thallus-final. London, United Kingdom: European Medicines Agecy. 2014. http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2015/07/WC500190398.pdf. Date Accessed 7-23-2018. Report No. EMA/HMPC/313675/2012. pp. 1-55.

8. European Medicines Agency (EMA). Bladderwrack: Fucus versiculosus L., thalus. London, United Kingdom: European Medicines Agency. 2016. http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Summary_of_assessment_report_for_the_public/2016/12/WC500217520.pdf. Date Accessed 7-23-2018. Report No. EMA/661584/2016. pp. 1-2.

9. European Food Safety Authority (EFSA) Panel on Dietetic Products, Nutrition and Allergies (NDA)Turck,D, Bresson J-L, Burlingame B, et al. Safety of Ecklonia cava phlorotannins as a novel food pursuant to Regulation (EC) No 258/97. EFSA Journal. 2017;15(10):5003-5018. http://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2017.5003.

10. Food Standards Australia New Zealand (FSANZ). Survey of inorganic arsenic in seaweed and seaweed-containing products available in Australia. 2013. http://www.foodstandards.gov.au/science/surveillance/Documents/Survey%20of%20inorganic%20arsenic%20in%20seaweed%20and%20seaweed%20.pdf. Date Accessed 4-3-2018.pp. 1-23.

11. Food Standards Australia New Zealand (FSANZ). Imported food risk statement: Hijiki seaweed and inorganic arsenic. 2016. https://www.foodstandards.gov.au/consumer/importedfoods/Documents/Hijiki%20seaweed%20and%20inorganic%20arsenic.pdf. Date Accessed 7-23-2018.pp. 1-8.

12. Lowe RL. Algal diversity and application. 2015. Unpublished information presented to the March 17 CIR Expert Panel. Washington D.C.

13. Bhutia TK, Petruzzello M, Pallardy R, and Rimsa C. Brown Algae. Encyclopaedia Britannica 2018. https://www.britannica.com/science/brown-algae. Last Updated 3-10-2018. Date Accessed 6-11-2018.

14. Fleurence J. Seaweed proteins: biochemical, nutritional spects and potential uses. Trends in Food Science & Technology. 1999;10(1):25-28.

15. Mori K, Ooi T, Hiraoka M, et al. Fucoxanthin and its metabolites in edible brown algae cultivated in deep seawater. Marine Drugs. 2004;2(2):63-72.

16. McHugh DJ. A guide to the seaweed industry. 2003. FAO Fisheries Technical Paper 441: pp.1-118. Rome, Italy: Food and Agriculture Organization of the United Nations.

17. Lüning K and Pang S. Mass cultivation of seaweeds: current aspects and approaches. Journal of Applied Phycology. 2003;15(2-3):115-119.

18. Borras-Chavez R, Edwards MS, Arvizu-Higuera DL, et al. Repetitive harvesting of Macrocystis pyrifera (Phaeophyceae) and its effects on chemical constituents of economic value. Botanica Marina. 2016;59(1):63-71.

19. Biotech Marine. 2015. Manufacturing process Alariane™ AD (Alaria Esculenta Extract in butylene glycol and water- dried before extraction). Unpublished data submitted by Personal Care Products Council.


http://webdictionary.personalcarecouncil.org/jsp/Home.jsp

http://www.annualreviews.org/doi/abs/10.1146/annurev.es.16.110185.001243?journalCode=ecolsys.1

http://online.personalcarecouncil.org/ctfa-static/online/lists/cir-pdfs/FR651.pdf

http://www.cir-safety.org/ingredients)

http://echa.europa.eu/registration-dossier/-/registered-dossier/7294



http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2015/07/WC500190398.pdf


http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Summary_of_assessment_report_for_the_public/2016/12/WC500217520.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Summary_of_assessment_report_for_the_public/2016/12/WC500217520.pdf

http://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2017.5003

http://www.foodstandards.gov.au/science/surveillance/Documents/Survey%20of%20inorganic%20arsenic%20in%20seaweed%20and%20seaweed%20.pdf

http://www.foodstandards.gov.au/science/surveillance/Documents/Survey%20of%20inorganic%20arsenic%20in%20seaweed%20and%20seaweed%20.pdf

http://www.foodstandards.gov.au/consumer/importedfoods/Documents/Hijiki%20seaweed%20and%20inorganic%20arsenic.pdf

http://www.britannica.com/science/brown-algae

http://www.britannica.com/science/brown-algae

20. Biotech Marine. 2015. Manufacturing process Juvenessence™ (Alaria Esculenta Extract in Caprylic Capric Triglycerides). Unpublished data submitted by Personal Care Products Council.

21. Solabia Group. 2017. Manufacturing Process Invincity® (trade name mixture containing Ascophyllum Nodosum Extract). Unpublished data submitted by Personal Care Products Council.

22. Solabia Group. 2017. Personal Care Products Council (PCPC) Unpublished Data: Manufacturing Process Invincinity® (trade name mixture containing Ascophyllum Nodosum Extract).

23. El Hattab M, Culioli G, Piovetti L, et al. Comparison of various extraction methods for identification and determination of volatile metabolites from the brown alga Dictyopteris membranacea. Journal of Chromatography A. 2007;1143(1-2):1-7.

24. Choi E-K, Park S-H, Ha K-C, et al. Clinical trial of the hypolipidemic effects of a brown alga Ecklonia cava extract in patients with hypercholesterolemia. International Journal of Pharmacology. 2015;11(7):798-805.

25. Biotech Marine. 2015. Manufacturing process Pyrenoine™ PF (Fucus Spiralis Extract in butylene glycol and water). Unpublished data submitted by Personal Care Products Council.

26. Anonymous. 2018. Method of manufacture and composition brown-algae-derived ingredients (Fucus Vesiculosis Extract and Hizikia Fusiforme Extract). Unpublished data submitted by Personal Care Products Council.

27. Biotech Marine. 2015. Manufacturing process Oleaphycol FV (Fucus Vesiculosis Extract in Caprylic/Capric Triglyceride). Unpublished data submitted by Personal Care Products Council.

28. Biotech Marine. 2017. Manufacturing process Oleaphycol LD (Laminaria Digitata Extract in Caprylic/Capric Triglyceride). Unpublished data submitted by Personal Care Products Council.

29. Ruxton CHS and Jenkins G. A novel topical ingredient derived from seaweed significantly reduces symptoms of acne vulgaris: A general literature review. Journal of Cosmetic Science. 2013;64(3):219-226.

30. Biotech Marine. 2017. Manufacturing process PhycolTM LD (Laminaria Digitata Extract water and propylene glycol). Unpublished data submitted by Personal Care Products Council.

31. Biotech Marine. 2017. Manufacturing process Phycoboreane™ 2C (Laminaria Hyperborea Extract in water). Unpublished data submitted by Personal Care Products Council on 9/11/18.

32. Active Concepts. 2013. AC Hydrating Seaweed Complex (mixture of Laminaria Japonica, Nereocystis Leutkeana and Macrocystis Pyrifera Extracts) manufacturing flow chart. Unpublished data submitted by Personal Care Products Council.

33. Biotech Marine. 2014. Manufacturing process Antileukin 6 (Laminaria Ochroleuca Extract in Caprylic/Capric Triglyceride). Unpublished data submitted by Personal Care Products Council on 9/11/18.

34. Biotech Marine. 2014. Manufacturing process Phlorogine (Laminaria Saccharina in Water and Propylene Glycol). Unpublished data submitted by Personal Care Products Council on 9/11/18.

35. Biotech Marine. 2009. Macrocystis Pyrifera DG (Macrocystis Pyrifera Extract- extracted in water with added Mcthylpropanediol). Unpublished data submitted by Personal Care Products Council.

36. Biotech Marine. 2017. Manufacturing process Phycol™ PC BG/PF (Pelvetia Caliculata Extract in Butylene Glycol and Water). Unpublished data submitted by Personal Care Products Council.

37. Biotech Marine. 2017. Manufacturing process Ambre Oceane™ 2C (Pelvetia Caliculata Extract in Water). Unpublished data submitted by Personal Care Products Council on 9/11/18.

38. Biotech Marine. 2015. Manufacturing process Ambre Oceane™ SPE (Pelvetia Caliculata Extract in Water). Unpublished data submitted by Personal Care Products Council on 9/11/18.

39. Biotech Marine. 2014. Manufacturing Process- Bioenergizer P BG (mixture of Pelvetia canaliculata and Laminaria digitata extracted in Butylene Glycol with Panthenol, with preservatives). Unpublished data submitted by Personal Care Products Council on 9/13/18.

40. Biotech Marine. 2014. Manufacturing Process- Bioenergizer P (mixture of Pelvetia canaliculata and Laminaria digitata extracted in Propylene Glycol with Panthenol). Unpublished data submitted by Personal Care Products Council on 9/13/18.

41. Bedoux G, Hardouin K, Burlot AS, and Bourgougnon N. Bioactive components from seaweeds: cosmetic applications and future development. Chapter: 12. In: Advances in Botanical Research. Vol. 71. Elsevier Ltd.; 2013:345-378.

42. Biotech Marine. 2014. Manufacturing Process- Ephemer™ (Undaria Pinnatifida Extract in Caprylic/Capric Triglyceride). Unpublished data submitted by Personal Care Products Council on 9/13/18.


43. Biotech Marine. 2016. Manufacturing Process- Phycol UP (Undaria Pinnatifida Extract in Water and Propylene Glycol). Unpublished data submitted by Personal Care Products Council on 9/13/18.

44. Fujimura T, Tsukahara K, Moriwaki S, et al. Treatment of human skin with an extract of Fucus vesiculosus changes in its thickness and mechanical properties. Journal of Cosmetic Science. 2002;53(1):1-9.

45. Simmons-Boyce JL, Purcell SL, Nelson CM, et al. Dietary Ascophyllum nodosum increases urinary excretion of tricarboxylic acid cycle intermediates in male Sprague-Dawley rats. Journal of Nutrition. 2009;139(8):1487-1494.

46. Jang WS and Choung SY. Antiobesity effects of the ethanol extract of Laminaria japonica Areshoung in high-fat-diet-induced obese rat. Evidence-Based Complementary and Alternative Medicine. 2013;2013(January):492807

47. Gideon TP and Rengasamy R. Toxicological evaluation of fucoidan from Cladosiphon okamuranus. Journal of Medicinal Food. 2008;11(4):638-642.

48. Sakakibara H, Nakagawa S, Wakameda H, et al. Effects of Japanese kelp (kombu) on life span of benzo[a]pyrene-fed mice. Journal of Nutritional Science and Vitaminology. 2005;51(5):369-373.

49. UNITIS. 2018. Safety report on brown algae-derived ingredients as used in cosmetics. Unpublished data submitted by Personal Care Products Council on 9/13/18.

50. Kang JY, Khan MNA, Park NH, et al. Antipyretic, analgesic, and anti-inflammatory activities of the seaweed Sargassum fluvellum and Sargassum thunbergii in mice. Journal of Ethnopharmacology. 2008;116(1):187-190.

51. Choi J-S, Moon WS, Choi JN, et al. Effects of seaweed Laminaria japonica extracts moisturizing activity in vivo. Journal of Cosmetic Science. 2013;64(3):193-205.

52. Hwang P-A, Yan M-D, Lin H-TV, et al. Toxicological evaluation of low molecular weight fucoidan in vitro and in vivo. Marine Drugs. 2016;14(7):E121

53. Yamashita Y. Method of removing inorganic arsenic from dried hijiki seaweed products. Nippon Suisan Gakkaishi. 2014;80(6):973-978.

54. Francesconi KA and Edmonds JS. Arsenic species in marine samples. Croatica Chemica Acta. 1998;71(2):343-359.

55. Kuehnelt D, Irgolic KJ, and Goessler W. Comparison of three methods for the extraction of arsenic compounds from the NRCC standard reference material DORM-2 and the brown alga Hijiki fuziforme. Applied Organometallic Chemistry. 2001;15(6):445-456.

56. Hamano-Nagaoka M, Hanaoka K, Usui M, et al. Nitric acid-based partial-digestion method for selective determination of inorganic arsenic in hijiki and application to soaked hijiki. Journal of Food Hygienic Society of Japan. 2008;49(2):88-94.

57. Katayama M, Sugawa-Katayama Y, and Murakami K. Pre-cooking of edible marine brown algae for reduction of arsenic contents. Journal of Food and Nutrition Sciences. 2015;3(1-2):84-87.

58. DavisTA, Volesky B, and Mucci A. A review of the biochemistry of heavy metal biosoption by brown algae. Water Research. 2003;37(18):4311-4330.

59. Gayinski M, Annick O, Thomas O, et al. Extraction, Purification, and NMR Analysis of Terpenes from Brown Algae. Methods in Molecular Biology. 2015;207-220.

60. Safe LM, Wong CJ, and Chandler RF. Sterols of marine algae. Journal of Pharmaceutical Sciences. 1974;63(3):464-466.

61. Lopes G, Sousa C, Bernardo J, et al. Sterol profiles in 18 macroalgae of the Portuguese coast. Journal of Phycology. 2011;47(5):1210-1218.

62. Güner A, Köksal Ç, Erel SB, et al. Antimicrobial and antioxidant activites with acute toxicity, cytotoxicity and mutagenicity of Cystoseira comprssa (Esper) Gerloff & Nizamuddin from the coast of Urla (Izmir, Turkey). Cytotechnology. 2015;67(1):135-143.

63. Andrade PB, Barbosa M, Matos RP, et al. Valuble compounds in macroalgae extracts. Food Chemistry. 2012;138(2-3):1819-1828.

64. Anonymous. 2018. Specifications, source and safety information Himanthalia Elongata Extract and Undaria Pinnatifida Extract (aqueous extracts). Unpublished data submitted by Personal Care Products Council on 11/5/18.

65. Anonymous. 2018. Specifications, source and safety information Halidrys Siliquosa Extract (aqueous extract). Unpublished data submitted by Personal Care Products Council on 11/5/18.

66. Chung H-J, Jeun J, Houng S-J, et al. Toxicological evaluation of fucoidan from Undaria pinnatifida in vitro and in vivo. Phytotherapy Research. 2010;24(7):1078-1083.

67. Hata Y, Nakajima K, Uchida J-I, et al. Clinical effects of brown seaweed, Undaria pinnatifida (wakame), on blood pressure in hypertensive subjects. Journal of Clinical Biochemistry and Nutrition. 2001;30(January):43-53.


68. Yoshi-Stark Y, Hsieh Y, and Suzuki T. Distribution of flavanoids and related compounds from seaweeds in Japan. Journal of Tokyo University of Fisheries. 2003;89:1-6.

69. Llorente-Mirandes T, Ruiz-Chancho MJ, Barbero M, et al. Determination of water-soluble arsenic compounds in commercial edible seaweed by LC-ICPMS. Journal of Agricultural and Food Chemistry. 2011;59(24):12963-12968.

70. Solabia Group. 2017. Specifications data sheet Invincity® (trade name mixture containing Ascophyllum Nodosum Extract). Unpublished data submitted by Personal Care Products Council.

71. Besada V, Andrade J, Schultze F, et al. Heavy metals in edible seaweeds commercialised for human consumption. Journal of Marine Systems. 2018;75(1-2):305-313.

72. Luoma SN, Bryan GW, and Langston WJ. Scavenging of heavy metals from particulates by brown seaweed. Marine Pollution Bulletin. 1982;13(11):394-396.

73. Giusti L. Heavy metal contamination of brown seaweed and sediments from the UK coastline between the Wear river and tees river. Environmental International. 2001;26(4):275-286.

74. Namikoshi M, Fujiwara T, Nishikawa T, et al. Natural abundance 14C content of dibutyl phthalate (DBP) from three marine algae. Marine Drugs. 2006;4(4):290-297.

75. U.S. Food and Drug Administration Center for Food Safety & Applied Nutrition (CFSAN). Voluntary Cosmetic Registration Program - Frequency of Use of Cosmetic Ingredients. College Park, MD: 2019. Obtained under the Freedom of Information Act from CFSAN; requested as "Frequency of Use Data".

76. Personal Care Products Council. 7-7-2015. Concentration of Use by FDA Product Category: Additional Algae-Derived Ingredients. Unpublished data submitted by Personal Care Products Council.

77. Personal Care Products Council. 2-16-2016. Concentration of Use by FDA Product Category: Brown Algae Additions. Unpublished data submitted by Personal Care Products Council.

78. Johnsen MA. The Influence of Particle Size. Spray Technology and Marketing. 2004;14(11):24-27. http://www.spraytechnology.com/index.mv?screen=backissues.

79. Rothe H. Special aspects of cosmetic spray safety evaluation. 2011. Unpublished information presented to the 26 September CIR Expert Panel. Washington D.C.

80. Bremmer HJ, Prud'homme de Lodder LCH, and van Engelen JGM. Cosmetics Fact Sheet: To assess the risks for the consumer; Updated version for ConsExpo 4. 2006. http://www.rivm.nl/bibliotheek/rapporten/320104001.pdf. Date Accessed 8-24-2011. Report No. RIVM 320104001/2006. pp. 1-77.

81. Rothe H, Fautz R, Gerber E, et al. Special aspects of cosmetic spray safety evaluations: Principles on inhalation risk assessment. Toxicol Lett. 8-28-2011;205(2):97-104. PM:21669261.

82. CIR Science and Support Committee of the Personal Care Products Council (CIR SSC). 11-3-2015. Cosmetic Powder Exposure. Unpublished data submitted by the Personal Care Products Council.

83. Aylott RI, Byrne GA, Middleton JD, et al. Normal use levels of respirable cosmetic talc: preliminary study. Int J Cosmet Sci. 1979;1(3):177-186. PM:19467066.

84. Russell RS, Merz RD, Sherman WT, et al. The determination of respirable particles in talcum powder. Food Cosmet Toxicol. 1979;17(2):117-122. PM:478394.

85. European Commission. CosIng database: following Cosmetic Regulation No. 1223/2009. http://ec.europa.eu/growth/tools-databases/cosing/. Last Updated 2018. Date Accessed 4-2-0018.

86. Brownlee I, Fairclough A, Sorsby A, and Paxman J. The potential health benefits of seaweed and seaweed extracts. Chapter: 6. Pomin V. In: Seaweed: Ecology, Nutrient, Composition and Medicinal Uses. Nova Science Publishers Inc.; 2019:

87. CEVA. Summary of edible seaweed and French regulation. 2014.

88. PDR for herbal medicines. 2 ed. Montvale, NJ: Medical Economics Company, Inc., 2000.

89. Committee on Herbal Medicinal Products (HMPC). Assessment report on Fucus vesiculosus L., thallus. London, United Kingdom: European Medicines Agency (EMA). 2014. http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2015/07/WC500190398.pdf. Date Accessed 7-23-2018. Report No. EMA/HMPC/313675/2012. pp. 1-55.

90. Bove M. Bladderwrack (fucus vesiculosus); and overview of the research and indications [pamphlet].Gaia Herbs; 1000.


http://www.spraytechnology.com/index.mv?screen=backissues

http://www.rivm.nl/bibliotheek/rapporten/320104001.pdf

http://ec.europa.eu/growth/tools-databases/cosing/



91. Solabia Group. 8-9-2018. Ascophyllum Nodosum Extract. Unpublished data submitted by Personal Care Products Council.

92. Yun J-W, Kim S-H, Kim Y-S, et al. Enzymatic extract from Ecklonia cava: acute and subchronic oral toxicity and genotoxicity studies. Regulatory Toxicology and Pharmacology. 2018;92(February):46-54.

93. Zaragozá MC, López D, Sáiz MP, et al. Toxicity and antioxidant activity in vitro and in vivo of two Fucus vesiculosus extracts. Journal of Agricultural and Food Chemistry. 2008;56(17):7773-7780.

94. Anonymous. 1997. Safety study summary: Acute oral, primary ocular irritation, primary skin irritation and repeat insult patch test. Unpublished data submitted by Personal Care Products Council on 11/27/18.

95. Michiels J, Skrivanova E, Missotten J, et al. Intact brown seaweed (Ascophyllum nodosum) in diets of weaned piglets: effects on performance, gut bacteria and morphology and plasma oxidative status. Journal of Animal Physiology and Animal Nutrition. 2012;96(6):1101-1111.

96. Yeo A-R, Lee J, Tae IH, et al. Anti-hyperlipidemic effect of polyphenol extract (Seapolynol™) and dieckol isolated from Ecklonia cava in in vivo and in vitro models. Preventive Nutrition and Food Science. 2012;17(1):1-7.

97. Funahashi H, Imai T, Mase T, et al. Seaweed prevents breast cancer? Japanese Journal of Cancer Research. 2001;92(5):483-487.

98. Funahashi H, Imai T, Tanaka Y, et al. Wakame seaweed suppresses the proliferation of 7,12-dimethylbenz(a)anthracene-induced mammary tumors in rats-. Japanese Journal of Cancer Research. 1999;90(9):922-927.

99. Vivotecnia. 2014. Summary: Bacterial reverse mutation test (Water, Fucus Spiralis Extract and Tetraselmis Chi Extract). Unpublished data submitted by the Personal Care Products Council on January 28, 2019.

100. Leite-Silva C, Gusmão CLS, and Takahashi CS. Genotoxic and antigenotoxic effects of Fucus vesiculosus extract on cultured human lymphocytes using the chromosome aberration and Comet assays. Genetics and Molecular Biology. 2007;30(1):105-111.

101. Lessonia. 2015. Safety certificate: Fucoreverse PF (contains 7% hydrolyzed fucoidan). Unpublished data submitted by Personal Care Products Council.

102. SafePharm Laboratories. 2005. Reverse mutation assay "Ames test" using Salmonella typhimurium (Laminaria Saccharina DJ- Laminaria Saccharina Extract in Sea Water and Methylpropanediol). Unpublished data submitted by Personal Care Products Council on 9/11/18.

103. Solabia Group. 10-23-2018. Macrocystis Pyrifera (Kelp) Extract. Unpublished data submitted by Personal Care Products Council on 10/23/18.

104. Active Concepts. 2016. Study summary: Bacterial reverse mutation test ACB Wakame Bioferment Advanced (Undaria Pinnatifida Cell Culture Extract). Unpublished data submitted by Personal Care Products Council on 10/3/18.

105. Anonymous. 2018. Specifications, source and safety information Cystoseira Amentacea/Caespitosa/Brachycarpa (aqueous extract). Unpublished data submitted by Personal Care Products Council on 11/5/18.

106. Ohigashi H, Sakai Y, Yamaguchi K, et al. Possible anti-tumor promoting properties of marine algae and in vivo activity of wakame seaweed extract. Bioscience, Biotechnology, and Biochemistry. 1992;56(6):994-995.

107. Son Y-S, Ullah HMA, Elfadl AK, et al. Inhibition of formation of azoxymethane-induced colonic aberrant crytp foci in rats by edible green algae Capsosiphon fulvescens and brown algae Hizikia fusiforme. In Vivo. 2018;32(1):101-108.

108. Teas J, Harbison ML, and Gelman RS. Dietary seaweed (Laminaria) and mammary carcinogenesis in rats. Cancer Research. 1984;44(7):2758-2761.

109. Zhang R-L, Luo W-D, Bi T-N, et al. Evaluation of antioxidant and immunity-enhancing activities of Sargassum pallidum aqueous extract in gastric cancer rats. Molecules. 2012;17(7):8419-8429.

110. Skibola CF, Curry JD, VandeVoort C, et al. Brown kelp modulates endocrine hormones in female Sprague-Dawley rats and in human luteinized granulosa cells. The Journal of Nutrition. 2005;135(2):296-300.

111. Zhang J, Riby JE, Conde L, et al. A Fucus vesiculosus extract inhibits extrogen receptor activation and induces cell death in female cancer cell lines. Complementary and Alternative Medicine. 2016;15(May):151 http://doi.org/10.1186/s12906-016-1129-6.

112. Piao MJ, Yoon WJ, Kang HK, et al. Protective effect of the ethyl acetate fraction of Sargassum miticum against ultraviolet B-irradiated damage in human keratinocytes. International Journal of Molecular Sciences. 2011;12(11):8146-8160.

113. Active Concepts. 2018. Study summaries: Dermal and ocular irritation tests ACB Wakame Bioferment Advanced (Undaria Pinnatifida Cell Culture Extract). Unpublished data submitted by Personal Care Products Council on 10/3/18.

114. Active Concepts. 2016. Dennal and ocular irritation tests AC Hydrating Seaweed Complex (mixture of Laminaria Japonica, Nereocystis Leutkeana and Macrocystis Pyrifera Extracts). Unpublished data submitted by Personal Care Products Council.


http://doi.org/10.1186/s12906-016-1129-6

115. Active Concepts. 2018. Dermal and ocular irritation tests (AC Algae Blend Sorb [contains 1.3% Sargassum Filipendula Extract]). Unpublished data submitted by Personal Care Products Council on 10/25/18.

116. Harrison Research Laboratories Inc. 1999. Repeated insult patch test Oleaphycol FV (Fucus Vesiculosis Extract in Caprylic/Capric Triglyceride). Unpublished data submitted by Personal Care Products Council.

117. Palmer Research. 2004. Etude de la tolérance cutanée aiguë d'une matière première chez le volontaire adulte: Patch-test 24 heures occlusif sous contrôle dermatologique. Phycol LD (Laminaria Digitata Extract in Propylene Glycol and water). Unpublished data submitted by Personal Care Products Council.

118. Palmer Research. 1996. Etude de la tolérance cutanée aiguë chez 10 volontaires adultes: Patch tests 24 et 48 heures, uniques: Phlorogine (Laminaria Saccharina Extract in Water and Propylene Glycol). Unpublished data submitted by Personal Care Products Council on 9/11/18.

119. Palmer Research. 2004. Etude de la tolérance cutanée aiguë d'une matière première chez le volontaire adulte: Patch-test 24 heures occlusif sous contrôle dermatologique. Phycol PC BG (Pelvetia Canaliculata in Propylene Glycol and water).

120. Palmer Research. 2004. Etude de Ia tolérance cutanée aiguë d'une matière première chez le volontaire adulte: Patch-test 24 heures occlusif sous contrôle dermatologique (Phycol UP- Undaria Pinnatifida Extract in Water and Propylene Glycol). Unpublished data submitted by Personal Care Products Council on 9/13/18.

121. Palmer Research. 1996. Etude de la tolérance cutanée aiguë chez 10 volontaires adultes Patchtests 24 et 48 heures, uniques (Bioenergizer P mixture of Pelvetia canaliculata and Laminaria digitata extracted in Propylene Glycol with Panthenol). Unpublished data submitted by Personal Care Products Council on 9/13/18.

122. Active Concepts. 2016. Study summary: In vitro skin senstization ACB Wakame Bioferment Advanced (Undaria Pinnatifida Cell Culture Extract). Unpublished data submitted by Personal Care Products Council on 10/3/18.

123. Active Concepts. 2016. Study summary: In chemico skin sensitization ACB Wakame Bioferment Advanced (Undaria Pinnatifida Cell Culture Extract). Unpublished data submitted by Personal Care Products Council on 10/3/18.

124. Anonymous. 2019. Summaries of Human Sensitization Studies of Products Containing Brown Algae-Derived Ingredients (Cystoseira Amentacea/Caespitosa/Brachycarpa Extract and Himanthalia Elongata Extract). Unpublished data submitted by the Personal Care Products Council on January 23, 2019.

125. UNITIS. 2019. Safety report on brown algae-derived ingredients as used in cosmetics. Unpublished data submitted by Personal Care Products Council on 1/03/2019.

126. Liskin. 2008. Study of the sensitizing capacity of a product according to the Marzulli-Maibach method (Kalpariane™- Alaria Esculenta Extract in Caprylic Capric Triglycerides). Unpublished data submitted by Personal Care Products Council.

127. Liskin. 2008. Study of the sensitizing capacity of a product according to the Marzulli-Maibach Method (Alariane- Alaria Esculenta Extract in butylene glycol and water). Unpublished data submitted by Personal Care Products Council.

128. Liskin. 2012. Sensitizing potential study of a product according to Marsulli-Maibach method (Juvenessence™- Alaria Esculenta Extract in Caprylic Capric Triglycerides). Unpublished data submitted by Personal Care Products Council.

129. Liskin. 2004. Evaluation of the irritating and sensitizing potential by 48-hours repeated application (Marzulli-Maibach method) Phlorgine (Laminaria Saccharina Extract in Water and Propylene Glycol). Unpublished data submitted by Personal Care Products Council on 9/11/18.

130. Harrison Research Laboratories Inc. 1997. Repeated insult patch test Pyrenonine sur Base BG (Fucus Spiralis Extract in water and butylene glycol). Unpublished data submitted by Personal Care Products Council.

131. CTI. 2014. Summary: Assessment of sensitizing potential and cutaneous compatibility on healthy adult volunteers according to the Marzulli-Maibach sensitization method Water, Fucus Spiralis Extract and Tetraselmis Chi Extract). Unpublished data submitted by the Personal Care Products Council on January 28, 2019.

132. Consumer Product Testing Co. 2013. Repeated insult patch test of a trade name mixture containing 0.1% Fucus Vesiculosus Extract (tested undiluted). Unpublished data submitted by the Personal Care Products Council on January 29, 2019.

133. Consumer Product Testing Co. 2016. Repeated insult patch test of a trade name mixture containing 0.1% Fucus Vesiculosus Extract ( l 0% dilution tested). Unpublished data submitted by the Personal Care Products Council on January 29, 2019.

134. Harrison Research Laboratories Inc. 1999. Repeated insult patch test Oleaphycol LD Laminaria Digitata Extract in Caprylic/Capric Triglyceride). Unpublished data submitted by Personal Care Products Council.

135. Anonymous. 1997. Repeated insult patch test (product 1 tested contains 8-12% Laminaria Digitata Extract). Unpublished data submitted by Personal Care Products Council on 11/27/18.


136. Essex Testing Clinic Inc. 2002. Clinical safety evaluation repeated insult patch test Pelvetiane (Ambre Oceane 2C- Pelvetia Canaliculata Extract in Water). Unpublished data submitted by Personal Care Products Council on 9/11/18.

137. Raben Production Group SRL. 2011. Assessment of sensitizing potential in the adult volunteer following the method ofMarzulli-Maibach (Water and Pelvetia Canaliculata Extract). Unpublished data submitted by the Personal Care Products Council on January 28, 2019.

138. Anonymous. 2007. Repeated insult patch test of a face cream containing 1.2% Sargassum Filipedula Extract. Unpublished data submitted by Personal Care Products Council.

139. Consumer Product Testing Co. 2014. Repeated insult patch test (eye cream containing 0.076% Sargassum Muticum Extract). Unpublished data submitted by Personal Care Products Council.

140. Consumer Product Testing Co. 2016. Repeated insult patch test (skin care product containing 0.076% Sargassum Muticum Extract). Unpublished data submitted by Personal Care Products Council.

141. Groupe Dermascan. 2014. Assessment of the sensitizing potential of a cosmetic product (Ephemer Undaria Pinnatifida Extract in Caprylic/Capric Triglyceride). Unpublished data submitted by Personal Care Products Council on 9/13/18.

142. Eurofins ATS. 2013. Summary: Assessment of the irritant potential of a test item after application to the embryonic hen's egg chorioallantoic membrane- HET-CAM (mixture containing Caprylic/Capric Triglyceride, Laminaria Ochroleuca Extract and Tocopherol). Unpublished data submitted by the Personal Care Products Council on January 24, 2019.

143. Solabia Group. 2017. Toxicological file Invincity® (trade name mixture containing Ascophyllum Nodosum Extract). Unpublished data submitted by Personal Care Products Council.

144. Consumer Product Testing Co. 2014. Ophthalmological in-use safety evaluation - 50% sensitive eyes (eye cream containing 0.076% Sargassum Muticum Extract). Unpublished data submitted by Personal Care Products Council.

145. Pye KG, Kelsey SM, House IM, et al. Severe dyserythropoisesis and autoimmune thrombocityopenia associated with ingestion of kelp supplements. Lancet. 1992;339(8808):1540

146. Amster E, Tiwary A, and Schenker MB. Case report: Potential arsenic toxicosis secondary to herbal kelp supplement. Environmental Health Perspectives. 2007;115(4):606-608.

147. Combet E, Ma ZF, Cousins F, et al. Low-level seaweed supplementation improves iodine status in iodine-insufficient women. British Journal of Nutrition. 2014;112(5):753-761.

148. Lee DH, Park MY, and Jeon HK. Effects of Ecklonia cava polyphenol in individuals with hypercholestrolemia: a pilot study. Journal of Medicinal Food. 2012. 15:(11): pp.1038-1044.

149. Skibola CF. The effect of Fucus vesiculosus, an edible brown seaweed, upon menstrual cycle length and hormonal status in three pre-menopausal women: a case report. BMC Complementary and Alternative Medicine. 2004;4(1):10

150. The Columbia Encyclopedia. Chrysophyta. https://www.encyclopedia.com/plants-and-animals/microbes-algae-and-fungi/moneran-and-protistan/chrysophyta. Last Updated 2018. Date Accessed 6-11-2018.

151. Encylopaedia Britannica. Dinoflagellate. https://www.britannica.com/science/dinoflagellate. Last Updated 2018. Date Accessed 6-11-2018.

152. Microsoft Encarta Online Encyclopedia 2000. Euglenoids. http://encarta.msn.com. Last Updated 2000. Date Accessed 6-11-2018.

153. Guiry MD. AlgaeBase. World-wide electronic publication. 2018. Galway, Ireland: National University of Ireland, Galway. http://www.algaebase.org/search/species/detail/?species_id=kfbb2c14027a14bf4&sk=0&from=results

154. Guiry MD. The Seaweed Site: information on marine algae. http://www.seaweed.ie/index.php. Last Updated 2018. Date Accessed 2-8-2018.

155. Gunnarsdóttir L. Masters. Rockweed (Ascophyllum nodosum) in Breidafjördur, Iceland: effects of environmental factors on biomass and plant height. 2017. pp.1-48. Reykjavik, Iceland: University of Iceland.

156. Food and Agricultural Organization (FAO) of the United Nations. Synopsis of biological data on knobbed wrack. Rome: 1970. http://www.fao.org/docrep/017/b0672e/b0672e.pdf. Date Accessed 2-7-2018. Report No. FAO Fisheries Synopsis No. 38 Rev. 1. pp. 1-50.

157. Balina K, Romagnoli F, and Blumberga D. Chemical composition and potential use of Fucus vesiculosus from Gulf of Riga. Energy Procedia. 2016;95(September):43-49.

158. Kain JM. Synopsis of biological data on Laminaria hyperborea. Rome: Food and Agriculture Organization of the United Nations. 1971. http://www.fao.org/docrep/017/c3845e/c3845e.pdf. Date Accessed 3-13-2018. Report No. FIRM/S87; SAST-Laminaria hyperborea-7,77(02)002.07. pp. 1-741.


http://www.encyclopedia.com/plants-and-animals/microbes-algae-and-fungi/moneran-and-protistan/chrysophyta

http://www.encyclopedia.com/plants-and-animals/microbes-algae-and-fungi/moneran-and-protistan/chrysophyta

http://www.britannica.com/science/dinoflagellate

http://encarta.msn.com/

http://www.algaebase.org/search/species/detail/?species_id=kfbb2c14027a14bf4&sk=0&from=results

http://www.seaweed.ie/index.php

http://www.fao.org/docrep/017/b0672e/b0672e.pdf

http://www.fao.org/docrep/017/c3845e/c3845e.pdf

159. Anderson BS and Hunt JW. Bioassay methods for evaluating the toxicity of heavy metals, biocides and sewage effluent using microscopic stages of giant kelp (Macrocystis pyrifera (Agardh): a preliminary report. Marine Environmental Research. 1988;26(2):113-134.

160. Graham MH, Vásquez JA, and Buschmann AH. Global ecology of the gian kelp Macrocystis: from ecotypes to ecosystems. Chapter: 2. Gibson, RN, Atkinson, RJA, and Gordon, JDM. In: Oceanography and Marine Biology. Vol. 45. 1 ed. Boca Raton, FL: CRC Press; 2007:39-88.

161. Acadian Seaplants Limited. Material safety data sheet: ACADIAN™ Organic Liquid Seaweed Concentrate; 0.1-0.0-5.0 [pamphlet]. Nova Scotia, Canada: 2012.

162. Grow More, Inc. Safety data sheet: seaweed extract (liquid). Ascophyllum Nodosum 84775-78-0 [pamphlet]. Gardena, CA: 2014.

163. Organic Ocean. ACTIV material safety data sheet [pamphlet]. Rimouski, Canada: Organic Ocean; 2015.

164. Acadian Seaplants Limited. Material safety data sheet: ASL™ Kelp Meal or Flour [pamphlet]. Nova Scotia, Canada: Acadian Seaplants Limited; 2004.

165. Natural Sourcing. Material safety data sheet: organic kelp powder (Ascophyllum nodosum) [pamphlet]. Oxford, CT: Natural Sourcing; 1000.

166. Chia Nan University of Pharmacy and Scienc. 2015. Patch testing of Ocean White® (20% Sargassum Glaucescens Extract, 79% water, 1% phenoxyethanol). Unpublished data submitted by Personal Care Products Council.

167. Güven KC, Percot A, and Sezik E. Alkaloids in marine algae. Marine Drugs. 2010;8(2):269-284.

168. Soares C, Machado S, Vieira EF, et al. Seaweeds from Portuguese coast: a potential food source. IOP Conference Series: Materials Science and Engineering. 2017;231(Conference 1):1-7.

169. Blunden G, Guiry MD, Druehl LD, et al. Trigonelline and other betaines in species of laminariales. Natural Product Communications. 2012;7(7):863-865.

170. Roleda MY, Skjermo J, Marfaing H, et al. Iodine content in bulk biomass of wild-harvested and cultivated edible seaweeds: inherent variations determine species-specific daily allowable consumption. Food Chemistry. 2018;254(July 15):333-339.

171. Council of Europe, European Pharmacopoeia Commission, and European Directorate for the Quality of Medicines & Healthcare. European pharmacopoeia. 7 ed. Strasbourg: Council of Europe: European Directorate for the Quality of Medicines and Healthcare, 2010.

172. Gall EA, Küpper FC, and Kloareg B. A survey of iodine content in Laminaria digitata. Botanica Mariana. 2004;47(1):30-37.

173. Kadam SU, Tiwari BK, and O'Donnell CP. Extraction, structure and biofunctional activities of laminarin from brown algae. International Journal of Food Science and Technology. 2015;50(1):24-31.

174. Fitton JH, Irhimeh M, and Falk N. Macroalgal fucoidan extracts: A new opportunity for marine cosmetics. Cosmetics & Toiletries Magazine. 2007;144(8):55-64.

175. Tarakhovskaya ER, Maslov YI, and Shishova MF. Phytohormones in algae. Russian Journal of Plant Physiology. 2007;54(2):163-170.

176. Lorenzo JM, Agregán R, Munekata PES, et al. Proximate composition and nutritional value of three macroalgae: Ascophyllum nodosum, Fucus vesiculosus and Bifurcaria bifurcata. Marine Drugs. 2017;15(11):360

177. Duke JA. Handbook of phytochemical constituents of GRAS herbs and other economic plants. http://phytochem.nal.usda.gov/phytochem/plants/show/933?et=. Boca Raton, FL. Last Updated 1992. Date Accessed 7-23-2018.

178. Active Concepts. 2018. Compositional breakdown ACB Wakame Bioferment Advanced (Undaria Pinnatifida Cell Culture Extract). Unpublished data submitted by Personal Care Products Council on 10/3/18.

179. Active Concepts. 2015. Compositional breakdown AC Phytogel (Hydrolyzed Fucus Vesiculosis Protein). Unpublished data submitted by Personal Care Products Council.

180. Active Concepts. 2018. Compositional breakdown AC Algae Blend Sorb (contains 1.3% Sargassum Filipendula Extract). Unpublished data submitted by Personal Care Products Council on 10/25/18.

181. Rose M, Lewis J, Langford N, et al. Arsenic in seaweed - forms, concentration and dietary exposure. Food and Chemical Toxicity. 2007;45(7):1263-1267.

182. Reis PA, Gonçalve J, Abreu H, et al. Seaweed Alaria esculenta as a biomonitor species of metal contamination in Aughinish Bay (Ireland). Ecological Indicators. 2016;69(October):19-25.

183. Biotech Marine. 2015. Alariane™ Physico-chemical data (Alaria Esculenta Extract in butylene glycol and water). Unpublished data submitted by Personal Care Products Council.


http://phytochem.nal.usda.gov/phytochem/plants/show/933?et=

184. Biotech Marine. 2015. Alariane™ AD Physico-chemical data (Alaria Esculenta Extract in butylene glycol and water- dried before extraction). Unpublished data submitted by Personal Care Products Council.

185. Biotech Marine. 2016. Kalpariane™ Physicochemical data (Alaria Esculenta Extract in Caprylic Capric Triglycerides). Unpublished data submitted by Personal Care Products Council.

186. Anonymous. 2019. Attestation on heavy metals for a mixture containing Water, Ascophyllum Nodosum Extract and Halopteris Scoparia Extract. Unpublished data submitted by the Personal Care Products Council on January 24, 2019.

187. Personal Care Products Council. 9-4-2018. Fucus Vesiculosis Extract and Hizikia Fusiforme Extract. Unpublished data submitted by Personal Care Products Council.

188. Biotech Marine. 2016. Oleaphycol FV Physico-chemical data (Fucus Vesiculosis Extract in Caprylic/Capric Triglyceride). Unpublished data submitted by Personal Care Products Council.

189. Anonymous. 2019. Attestation on heavy metals for a mixture containing Water and Fucus Serratus Extract. Unpublished data submitted by the Personal Care Products Council on January 24, 2019.

190. Biotech Marine. 2015. Pyrenoine™ Physico-chemical data (Fucus Spiralis Extract in butylene glycol and water). Unpublished data submitted by Personal Care Products Council.

191. Anonymous. 2019. Attestation on heavy metals for a mixture containing Water, Fucus Spiralis Extract and Tetraselmis Chi Extract. Unpublished data submitted by the Personal Care Products Council on January 28, 2019.

192. Anonymous. 2019. Attestation on heavy metals for a mixture containing Water, Himanthalia Elongata Extract, Fucus Vesiculosus Extract and Saccharomyces Cerevisiae Extract. Unpublished data submitted by the Personal Care Products Council on January 24, 2019.

193. Biotech Marine. 2017. Oleaphycol LD Physico-chemical data (Laminaria Digitata Extract in Caprylic/Capric Triglyceride). Unpublished data submitted by Personal Care Products Council.

194. Biotech Marine. 2005. Oleaphycol LD Physico-chemical data (Laminaria Digitata Extract in water and propylene glycol). Unpublished data submitted by Personal Care Products Council.

195. Active Concepts. 2018. Compositional breakdown AC Hydrating Seaweed Complex (mixture of Laminaria Japonica, Nereocystis Leutkeana and Macrocystis Pyrifera Extracts). Unpublished data submitted by Personal Care Products Council.

196. Biotech Marine. 2017. Phycoboreane™ 2C (Laminaria Hyperborea Extract in water) Physicochemical data. Unpublished data submitted by Personal Care Products Council on 9/11/18.

197. Anonymous. 2019. Attestation on heavy metals for a mixture containing Caprylic/Capric Triglyceride, Laminaria Ochroleuca Extract and Tocopherol. Unpublished data submitted by the Personal Care Products Council on January 24, 2019.

198. Biotech Marine. 2016. Phlorogine™ (Laminaria Saccharina Extract in Water and Propylene Glycol) Physico-chemical data. Unpublished data submitted by Personal Care Products Council on 9/11/18.

199. Personal Care Products Council. 9-11-2018. Laminaria Saccharina Extract. Unpublished data submitted by Personal Care Products Council on 9/11/18.

200. Anonymous. 2019. Attestation on heavy metals for a mixture containing Water, Butylene Glycol and Lessonia Nigrescens Extract. Unpublished data submitted by the Personal Care Products Council on January 24, 2019.

201. Anonymous. 2019. Attestation on heavy metals for a mixture containing Water and Pelvetia Canaliculata Extract. Unpublished data submitted by the Personal Care Products Council on January 28, 2019.

202. Biotech Marine. 2017. Phycol™ PC BG/PF (Pelvetia Canaliculata Extract in Butylene Glycol and Water) Physico-chemical data. Unpublished data submitted by Personal Care Products Council.

203. Biotech Marine. 2018. Ambre Oceane™ SPE (Pelvetia Canaliculata Extract in Water) Physicochemical data. Unpublished data submitted by Personal Care Products Council on 9/11/18.

204. Biotech Marine. 2015. Ambre Oceane™ 2C (Pelvetia Canaliculata Extract in Water) Physicochemical data. Unpublished data submitted by Personal Care Products Council on 9/11/18.

205. Personal Care Products Council. 9-13-2018. Pelvetia Canaliculata Extract and Laminaria Digitata Extract. Unpublished data submitted by Personal Care Products Council on 9/13/18.

206. Personal Care Products Council. 2018. Material specification Sargassum Glaucescens Extract. Unpublished data submitted by Personal Care Products Council.


207. Anonymous. 2019. Attestation on heavy metals for a mixture containing Water, and Sargassum Muticum Extract. Unpublished data submitted by the Personal Care Products Council on January 28, 2019.

208. Personal Care Products Council. 10-3-2018. Undaria Pinnatifida Cell Culture Extract. Unpublished data submitted by Personal Care Products Council on 10/3/18.

209. Biotech Marine. 2008. Phycol® UP (Undaria Pinnatifida Extract in Water and Propylene Glycol) Physico-chemical data. Unpublished data submitted by Personal Care Products Council on 9/13/18.

210. Biotech Marine. 2016. Ephemer™ (Undaria Pinnatifida Extract in Caprylic/Capric Triglyceride) Physico-chemical data. Unpublished data submitted by Personal Care Products Council on 9/13/18.

211. Personal Care Products Council. 2-19-0019. Concentration of Use by FDA Product Category - Brown Algae. Additional Concentration of Use Information - Halidrys Siliquosa Extract. Unpublished data submitted by the Personal Care Products Council on February 19, 2019.

212. MacArtain P, Gill C, Brooks M, et al. Nutritional Value of Edible Seaweeds. Nutrition Reviews. 2007;65(12):535-543.

213. Cofrades S, López-López I, Bravo L, et al. Nutritional and Antioxidant Properties of Different Brown and Red Spanish Edible Seaweeds. Food Science and Technology International. 2010;16(5)

214. Guiry MD. Use of seaweed as food in Ireland. http://www.seaweed.ie/uses_ireland/irishseaweedfood.php. Last Updated 2019. Date Accessed 2-14-2019.

215. Marhuenda J, Gironés-Vilaplana A, Galvez M, et al. Antioxidant capacity and total phenolics in different types of edible seaweed after three times of cooking. Agro Food Industry Hi Tech. 2016;27(2):57-59.

216. Institut Pasteur de Lille. 2014. In vitro skin irritation: Reconstructed human epidermis test method Ephemer™ (Undaria Pinnatifida Extract in Caprylic/Capric Triglyceride). Unpublished data submitted by Personal Care Products Council on 9/13/18.

217. Laboratoire Cosderma. 2007. Verification in humans of the skin compatibility of a cosmetic product after single application under dressing 24 hour patch test Olea Alaria ( <5% Alaria Esculenta Extract; >95% Caprylic/Capric Triglycerides). Unpublished data submitted by Personal Care Products Council.

218. Eurofins A TS. 2006. Summary: Evaluation ofthe cutaneous tolerance of a cosmetic product after a single application under occlusive patch during 48 hours: patch test method (mixture containing Water, Ascophyllum Nodosum Extract and Halopteris Scoparia Extract). Unpublished data submitted by the Personal Care Products Council on January 24, 2019.

219. Eurofins ATS. 2005. Summary: Evaluation of the cutaneous tolerance of a cosmetic product after a single application under occlusive patch during 48 hours: patch test method (mixture Water and Fucus Serratus Extract). Unpublished data submitted by the Personal Care Products Council on January 24, 2019.

220. Palmer Research. 2004. Etude de la tolérance cutanée aiguë d'une matière première chez le volontaire adulte: Patch-test 24 heures occlusif sous contrôle dermatologique. Pyrenoine (Fucus Spiralis Extract in water and butylene glycol). Unpublished data submitted by Personal Care Products Council on 9/10/18.

221. Eurofins ATS. 2011. Summary: Evaluation of skin tolerance of a cosmetic product after a single application under occluded patch during 48h on 14 volunteers: 48 hours patch test (Water, Fucus Spiralis Extract and Tetraselmis Chi Extract). Unpublished data submitted by the Personal Care Products Council on January 28, 2019.

222. EVIC France. 2016. Summary: Human patch test under dermatological control (mixture containing Water, Himanthalia Elongata Exract, Fucus Vesiculosus Extract and Saccharomyces Cerevisiae Extract). Unpublished data submitted by the Personal Care Products Council on January 24, 2019.

223. Palmer Research. 2004. Etude de la tolérance cutanée aiguë d'une matière première chez le volontaire adulte: Patch-test 24 heures occlusif sous contrôle dermatologique. Oleaphycol LD (Laminaria Digitata Extract in Caprylic/Capric Triglyceride). Unpublished data submitted by Personal Care Products Council.

224. Laboratoire Cosderma. 2010. Checking on human beings of the cutaneous tolerance of a cosmetic product after single application under patch: Patch test 24h (Phycoboreane™ 2C - Laminaria Hyperborea Extract in water). Unpublished data submitted by Personal Care Products Council on 9/11/18.

225. DECS Investigation Clinique. 1999. Study of acute skin tolerance in adult volunteers: 24-hour patch test: Antileukine 6 (Laminaria Ochroleuca Extract in Caprylic/Capric Triglyceride). Unpublished data submitted by Personal Care Products Council on 9/11/18.

226. Eurofins ATS. 2013. Summary: Assessment of skin tolerance of a cosmetic product after a single application under occluded patch test during 48 H on I 0 volunteers: 48 hours patch test (mixture containing Caprylic/Capric Triglyceride, Larninaria Ochroleuca Extract and Tocopherol). Unpublished data submitted by the Personal Care Products Council on January 24, 2019.


http://www.seaweed.ie/uses_ireland/irishseaweedfood.php

227. Eurofins ATS. 2005. Summary: Evaluation de Ia tolerance cutanee d'un produit cosmetique apres application unique sous pansement occlusif pendant 48 heurs: methode des patchs tests (mixture Water, Butylene Glycol and Lessonia Nigrescens Extract). Unpublished data submitted by the Personal Care Products Council on January 24, 2019.

228. Palmer Research. 2004. Etude de la tolérance cutanée aiguë d'une matière première chez le volontaire adulte: Patch-test 24 heures occlusif sous contrôle dermatologique. (Phycol PC BG Pelvetia Canaliculata Extract in Butylene Glycol and Water). Unpublished data submitted by Personal Care Products Council.

229. Eurofins ATS. 2006. Summary: Evaluation of the cutaneous tolerance of a cosmetic product after a single application under occlusive patch during 48 hours: patch test method (Water and Pelvetia Canaliculata Extract). Unpublished data submitted by the Personal Care Products Council on January 28, 2019.

230. Eurofins ATS. 2006. Summary: Evaluation of the cutaneous tolerance of a cosmetic product after a single application under occlusive patch during 48 hours: patch test method (Water, and Sargassum Muticum Extract). Unpublished data submitted by the Personal Care Products Council on January 28, 2019.

231. Active Concepts. 2018. OECD TG 442D: In vitro skin sensitization (AC Algae Blend Sorb [contains 1.3% Sargassum Filipendula Extract]). Unpublished data submitted by Personal Care Products Council on 10/25/18.

232. Consumer Product Testing Co. 2013. Repeated insult patch test- night moisturizer containing 0.05% Alaria Esculenta Extract. Unpublished data submitted by Personal Care Products Council.

233. UNITIS. 2019. Safety reports on Brown-Algae Derived Ingredients as Used in Cosmetics (addition of some dose volume information for HRIPTs). Unpublished data submitted by Personal Care Products Council on 03/14/2019.

234. Eurofins A TS. 2006. Summary: Evaluation of a product through its application on the chorioallantoic membrane of a chicken eggshell: Het Cam method (mixture Water, Ascophyllum Nodosum Extract and Halopteris Scoparia Extract). Unpublished data submitted by the Personal Care Products Council on January 24, 2019.

235. Eurofins ATS. 2005. Summary: Evaluation of a potential irritancy of a product through its application on the chorioallantoic membrane of a chicken eggshell: Het Cam method (mixture Water and Fucus Serratus Extract). Unpublished data submitted by the Personal Care Products Council on January 24, 2019.

236. EVIC France. 2016. Summary: Assessment of the irritant potential of a test item after application to the embryonic hen's egg chorioallantoic membrane - HET-CAM (mixture containing Water, Himanthalia Elongata Exract, Fucus Vesiculosus Extract and Saccharomyces Cerevisiae Extract). Unpublished data submitted by the Personal Care Products Council on January 24, 2019.

237. Consumer Product Testing Co. 2006. The Hen's Egg Test - Utilizing the Chorioallantoic Membrane (HET-CAM) (product 1 tested contains 8-12% Laminaria Digitata Extract). Unpublished data submitted by Personal Care Products Council on 11/27/18.

238. Eurofins ATS. 2005. Summary: Evaluation du potentiel irritant d'un produit par application sur la membrane chorio-allantoidienne do l'oeuf de poule: methode du Het Cam (mixture Water, Butylene Glycol and Lessonia Nigrescens Extract). Unpublished data submitted by the Personal Care Products Council on January 24, 2019.

239. Eurofins ATS. 2006. Summary: Evaluation of the potential irritancy of a product through its application on the chorioallantoic membrane of a chicken eggshell: Het Cam Method (Water, and Sargassum Muticum Extract). Unpublished data submitted by the Personal Care Products Council on January 28, 2019.

240. Conz PA, La Greca G, Benedetti P, et al. Fucus vesiculosus: a nephrotoxic algae? Nephrology, Dialysis, Transplantation. 1998;13(2):526-527.


2019 FDA VCRP Data

1. Agarum Cribrosum Extract*

12C - Face and Neck (exc shave) 1

2. Alaria Esculenta Extract*

03C - Eye Shadow 8 03D - Eye Lotion 2 03G - Other Eye Makeup Preparations 2 05I - Other Hair Preparations 1 07A - Blushers (all types) 6 07B - Face Powders 5 07C - Foundations 1 07E - Lipstick 3 07I - Other Makeup Preparations 1 12C - Face and Neck (exc shave) 4 12D - Body and Hand (exc shave) 2 12F - Moisturizing 6

3. Ascophyllum Nodosum

NONE

4. Ascophyllum Nodosum Extract*

03D - Eye Lotion 8 03G - Other Eye Makeup Preparations 9 05A - Hair Conditioner 6 05F - Shampoos (non-coloring) 3 05G - Tonics, Dressings, and Other Hair Grooming Aids 4 07B - Face Powders 1 07F - Makeup Bases 2 08B - Cuticle Softeners 1 08G - Other Manicuring Preparations 2 10A - Bath Soaps and Detergents 6 11A - Aftershave Lotion 1 11E - Shaving Cream 1 12A - Cleansing 5 12C - Face and Neck (exc shave) 58 12D - Body and Hand (exc shave) 4 12F - Moisturizing 16 12G - Night 2


12H - Paste Masks (mud packs) 8 12I - Skin Fresheners 1 12J - Other Skin Care Preps 2

5. Ascophyllum Nodosum Powder*

02A - Bath Oils, Tablets, and Salts 1 12A - Cleansing 1 12F - Moisturizing 2 12J - Other Skin Care Preps 1

6. Cladosiphon Novae-Caledonia Extract

NONE

7. Cladosiphon Okamuranus Extract*

03G - Other Eye Makeup Preparations 1 07C - Foundations 1 12A - Cleansing 1 12C - Face and Neck (exc shave) 3 12F - Moisturizing 2 12G - Night 2

8. Cystoseira Amentacea/Caespitosa/Branchycarpa Extract

12A - Cleansing 1 ^^Cystoseira Foeniculacea/brachycarpa extract


None


None


None


None


None



None

15. Dictyopteris Polypodioides Extract*

12C - Face and Neck (exc shave) 1 12F - Moisturizing 4 12H - Paste Masks (mud packs) 1

16. Dictyota Coriacea Extract

None

17. Durvillaea Antarctica Extract*

None

18. Ecklonia Cava Extract

01B - Baby Lotions, Oils, Powders, and Creams 1 03D - Eye Lotion 1 05F - Shampoos (non-coloring) 1 12C - Face and Neck (exc shave) 8 12F - Moisturizing 5 12H - Paste Masks (mud packs) 2

19. Ecklonia Cava Water

None

20. Ecklonia Kurome Extract

None

21. Ecklonia Kurome Powder

None


None

23. Ecklonia Maxima Extract

None

24. Ecklonia Maxima Powder

None

25. Ecklonia Radiata Extract*


05A - Hair Conditioner 36 05B - Hair Spray (aerosol fixatives) 7 05F - Shampoos (non-coloring) 30 05G - Tonics, Dressings, and Other Hair Grooming Aids 6 05H - Wave Sets 3

26. Eisenia Arborea Extract

None

27. Fucus Serratus Extract*

03D - Eye Lotion 1 12C - Face and Neck (exc shave) 4 12F - Moisturizing 2 12G - Night 1

28. Fucus Spiralis Extract

None

29. Fucus Vesiculosus*

None

30. Fucus Vesiculosus Extract*

02A - Bath Oils, Tablets, and Salts 3 02B - Bubble Baths 2 02D - Other Bath Preparations 4 03D - Eye Lotion 2 03F - Mascara 2 03G - Other Eye Makeup Preparations 1 04E - Other Fragrance Preparation 3 05A - Hair Conditioner 10 05C - Hair Straighteners 2 05F - Shampoos (non-coloring) 9 05G - Tonics, Dressings, and Other Hair Grooming Aids 6 05I - Other Hair Preparations 2 07F - Makeup Bases 2 07I - Other Makeup Preparations 1 10A - Bath Soaps and Detergents 25 10E - Other Personal Cleanliness Products 5 11A - Aftershave Lotion 1 11E - Shaving Cream 1


11F - Shaving Soap 1 11G - Other Shaving Preparation Products 1 12A - Cleansing 12 12B - Depilatories 1 12C - Face and Neck (exc shave) 45 12D - Body and Hand (exc shave) 32 12E - Foot Powders and Sprays 1 12F - Moisturizing 44 12G - Night 1 12H - Paste Masks (mud packs) 23 12I - Skin Fresheners 4 12J - Other Skin Care Preps 19 13B - Indoor Tanning Preparations 25 13C - Other Suntan Preparations 1

31. Fucus Vesiculosus Powder*

02A - Bath Oils, Tablets, and Salts 1 12C - Face and Neck (exc shave) 1 12H - Paste Masks (mud packs) 2


None


None

34. Himanthalia Elongata Extract*

03G - Other Eye Makeup Preparations 1 05A - Hair Conditioner 2 05I - Other Hair Preparations 1 12C - Face and Neck (exc shave) 2 12D - Body and Hand (exc shave) 5 12F - Moisturizing 2 12H - Paste Masks (mud packs) 1


None

36. Hizikia Fusiforme Extract


None

37. Hizikia Fusiformis Water

None


None


None


None


None

42. Laminaria Cloustoni Extract*

03D - Eye Lotion 1 07F - Makeup Bases 1 12A - Cleansing 3 12C - Face and Neck (exc shave) 4 12F - Moisturizing 3 12G - Night 1 12H - Paste Masks (mud packs) 1 12I - Skin Fresheners 1


None

44. Laminaria Digitata Extract*

02A - Bath Oils, Tablets, and Salts 2 02B - Bubble Baths 3 02D - Other Bath Preparations 2 03D - Eye Lotion 5 03E - Eye Makeup Remover 2 03F - Mascara 4 03G - Other Eye Makeup Preparations 9 04E - Other Fragrance Preparation 2 05A - Hair Conditioner 4 05B - Hair Spray (aerosol fixatives) 1


05F - Shampoos (non-coloring) 12 05G - Tonics, Dressings, and Other Hair Grooming Aids 17 05I - Other Hair Preparations 2 06H - Other Hair Coloring Preparation 1 07B - Face Powders 2 07C - Foundations 3 07E - Lipstick 1 07F - Makeup Bases 1 07I - Other Makeup Preparations 3 09A - Dentifrices 1 10A - Bath Soaps and Detergents 8 10C - Douches 1 10E - Other Personal Cleanliness Products 5 11A - Aftershave Lotion 4 12A - Cleansing 21 12C - Face and Neck (exc shave) 49 12D - Body and Hand (exc shave) 39 12F - Moisturizing 40 12G - Night 6 12H - Paste Masks (mud packs) 19 12I - Skin Fresheners 3 12J - Other Skin Care Preps 33 13A - Suntan Gels, Creams, and Liquids 4 13C - Other Suntan Preparations 1

45. Laminaria Digitata Powder*

02A - Bath Oils, Tablets, and Salts 1 02D - Other Bath Preparations 2 05A - Hair Conditioner 1 05F - Shampoos (non-coloring) 2 10E - Other Personal Cleanliness Products 1 12C - Face and Neck (exc shave) 1 12H - Paste Masks (mud packs) 9 12J - Other Skin Care Preps 1

46. Laminaria Hyperborea Extract*

04E - Other Fragrance Preparation 2 05I - Other Hair Preparations 1 10A - Bath Soaps and Detergents 1 12C - Face and Neck (exc shave) 2 12D - Body and Hand (exc shave) 1


12F - Moisturizing 7 12J - Other Skin Care Preps 1

47. Laminaria Japonica Extract*

01B - Baby Lotions, Oils, Powders, and Creams 2 03D - Eye Lotion 2 03F - Mascara 1 03G - Other Eye Makeup Preparations 1 05F - Shampoos (non-coloring) 2 07A - Blushers (all types) 2

07B - Face Powders 3 07C - Foundations 7 07E - Lipstick 1 07F - Makeup Bases 2 08G - Other Manicuring Preparations 2 10A - Bath Soaps and Detergents 3 10E - Other Personal Cleanliness Products 2 12A - Cleansing 3 12C - Face and Neck (exc shave) 38 12D - Body and Hand (exc shave) 2 12F - Moisturizing 12 12G - Night 2 12H - Paste Masks (mud packs) 7 12J - Other Skin Care Preps 4


None

49. Lamniara Logissima Extract

None

50. Laminaria Ochroleuca Extract*

03C - Eye Shadow 2 03D - Eye Lotion 3 03E - Eye Makeup Remover 2 07B - Face Powders 3 07C - Foundations 2 07E - Lipstick 1 07I - Other Makeup Preparations 2 10E - Other Personal Cleanliness Products 2


12A - Cleansing 1 12C - Face and Neck (exc shave) 8 12D - Body and Hand (exc shave) 4 12F - Moisturizing 15 12H - Paste Masks (mud packs) 1 12J - Other Skin Care Preps 7 13B - Indoor Tanning Preparations 1

51. Laminaria Saccharina Extract*

05A - Hair Conditioner 4 05F - Shampoos (non-coloring) 4 05G - Tonics, Dressings, and Other Hair Grooming Aids 4 07C - Foundations 9 07I - Other Makeup Preparations 2 10A - Bath Soaps and Detergents 2 10E - Other Personal Cleanliness Products 2 11A - Aftershave Lotion 4 11D - Preshave Lotions (all types) 1 11E - Shaving Cream 1 12A - Cleansing 26 12C - Face and Neck (exc shave) 20 12F - Moisturizing 35 12G - Night 1 12H - Paste Masks (mud packs) 7 12I - Skin Fresheners 2 12J - Other Skin Care Preps 12

52. LEssonia Nigrescens Extract*

None


None

54. Macrocystis Pyrifera (Kelp)*

10A - Bath Soaps and Detergents 1 12F - Moisturizing 1

55. Macrocystis Pyrifera (Kelp) Extract*

01B - Baby Lotions, Oils, Powders, and Creams 1 02A - Bath Oils, Tablets, and Salts 3 02B - Bubble Baths 1


03D - Eye Lotion 1 03E - Eye Makeup Remover 1 03G - Other Eye Makeup Preparations 3 04E - Other Fragrance Preparation 7 05A - Hair Conditioner 10 05B - Hair Spray (aerosol fixatives) 3 05F - Shampoos (non-coloring) 12 05G - Tonics, Dressings, and Other Hair Grooming Aids 20 05H - Wave Sets 1 05I - Other Hair Preparations 10 06H - Other Hair Coloring Preparation 4 07A - Blushers (all types) 2 07B - Face Powders 2 07C - Foundations 3 07H - Makeup Fixatives 1 08A - Basecoats and Undercoats 2 08E - Nail Polish and Enamel 2 08G - Other Manicuring Preparations 1 10A - Bath Soaps and Detergents 21 10E - Other Personal Cleanliness Products 14 11A - Aftershave Lotion 2 11E - Shaving Cream 1 12A - Cleansing 6 12B - Depilatories 6 12C - Face and Neck (exc shave) 14 12D - Body and Hand (exc shave) 13 12F - Moisturizing 16 12G - Night 1 12H - Paste Masks (mud packs) 5 12I - Skin Fresheners 3 12J - Other Skin Care Preps 7


None


None

58. Macrocystis Pyrifera (Kelp) Protein*

10A - Bath Soaps and Detergents 1 12H - Paste Masks (mud packs) 1


12J - Other Skin Care Preps 1


07A - Blushers (all types) 1 07B - Face Powders 2 07C - Foundations 3

60. Pelvetia Canaliculata Extract*

03D - Eye Lotion 1 03F - Mascara 3 03G - Other Eye Makeup Preparations 2 05A - Hair Conditioner 4 05B - Hair Spray (aerosol fixatives) 1 05F - Shampoos (non-coloring) 6 05G - Tonics, Dressings, and Other Hair Grooming Aids 12 05I - Other Hair Preparations 1 06H - Other Hair Coloring Preparation 1 10E - Other Personal Cleanliness Products 1 12A - Cleansing 1 12C - Face and Neck (exc shave) 8 12F - Moisturizing 4 12G - Night 2

61. Pelvetia Siliquosa Extract

None

62. Phyllacantha Fibrosa Extract

None


None


None


05A - Hair Conditioner 1 05F - Shampoos (non-coloring) 1


66. Sargassum Filipendula Extract*

03D - Eye Lotion 2 05A - Hair Conditioner 1 05B - Hair Spray (aerosol fixatives) 3 05F - Shampoos (non-coloring) 2 05G - Tonics, Dressings, and Other Hair Grooming Aids 1 06A - Hair Dyes and Colors (all types requiring caution statements and patch tests) 23 07I - Other Makeup Preparations 1 11F - Shaving Soap 1 12A - Cleansing 2 12C - Face and Neck (exc shave) 1 12F - Moisturizing 4 12H - Paste Masks (mud packs) 3 12J - Other Skin Care Preps 2

67. Saragassum Fulvellum Extract

12C - Face and Neck (exc shave) 2

68. Sargassum Fusiforme Extract*

01B - Baby Lotions, Oils, Powders, and Creams 1 03G - Other Eye Makeup Preparations 1 12C - Face and Neck (exc shave) 4 12F - Moisturizing 7 12H - Paste Masks (mud packs) 4


None


None

71. Sargassum Muticum Extract*

12H - Paste Masks (mud packs) 1


None


73. Saragssum SIliquastrum Extract

None


None

75. Sargassum Vugare Extract*

None

76. Sphacelaria Scoparia Extract*

10A - Bath Soaps and Detergents 2 12D - Body and Hand (exc shave) 4 12F - Moisturizing 1 12J - Other Skin Care Preps 1

77. Undaria Peterseniania Extract

None


None


None

80. Undaria Pinnatifida Extract*

01A - Baby Shampoos 1 01B - Baby Lotions, Oils, Powders, and Creams 3 03D - Eye Lotion 4 05A - Hair Conditioner 2 05F - Shampoos (non-coloring) 5 05I - Other Hair Preparations 2 07B - Face Powders 2 07C - Foundations 3 07I - Other Makeup Preparations 2 10A - Bath Soaps and Detergents 1 10E - Other Personal Cleanliness Products 3 12A - Cleansing 1 12C - Face and Neck (exc shave) 29 12D - Body and Hand (exc shave) 13 12F - Moisturizing 14


12G - Night 4 12H - Paste Masks (mud packs) 1

81. Undaria Pinnatifida Powder*

None


None

Other:

Laminaria Extract*

05C - Hair Straighteners 1 05F - Shampoos (non-coloring) 1 12A - Cleansing 1 12D - Body and Hand (exc shave) 1 12J - Other Skin Care Preps 1


Concentration of Use by FDA Product Category – Brown Algae Additional Concentration of Use Information – Halidrys Siliquosa Extract

Product Category Maximum Concentration of Use Eye lotions 0.29% Foundations 0.29% Skin Cleansing (cold creams, cleansing lotions, liquids and pads) 0.029% Face and neck products Not spray

0.29%

Night products Not spray

0.29%

Information provided in 2019 Table prepared February 19, 2019


Ingredient (37) GRAS Food Tox Sensitization data Ascophyllum Nodosum Extract ✔ ✔ - 4 week oral ✔ Fucus Vesiculosus Extract ✔ ✔ - 4 week oral ✔ Himanthalia Elongata Extract ✔ ✔ Undaria Pinnatifida Extract ✔ ✔ ✔ - 32 week oral ✔ Undaria Pinnatifida Cell Culture Extract

✔ ✔ ✔

Macrocystis Pyrifera (Kelp) Extract ✔ ✔ ✔ Alaria Esculenta Extract ✔ ✔ Laminaria Digitata Extract ✔ ✔ ✔ Laminaria Saccharina Extract ✔ ✔ ✔ Undaria Pinnatifida Powder ✔ ✔ ✔ - 36 week oral Laminaria Diabolica Extract (synonymous with Laminaria Japonica Extract, Laminaria Ochroleuca Extract, and Saccharina Japonica Extract)

✔ ✔ ✔ - 6 week oral

Laminaria Japonica Extract (synonymous with Laminaria Diabolica Extract, Laminaria Ochroleuca Extract, and Saccharina Japonica Extract)


Laminaria Ochroleuca Extract (synonymous with Laminaria Diabolica Extract, Laminaria Japonica Extract, and Saccharina Japonica Extract)


Saccharina Japonica Extract (synonymous with Laminaria Diabolica Extract, Laminaria Japonica Extract, and Laminaria Ochroleuca Extract)


Laminaria Japonica Powder

✔ ✔ ✔ - lifetime oral

Cladosiphon Okamuranus Extract ✔ ✔ - 3 month oral Ecklonia Cava Extract ✔ ✔ - 13 week oral Macrocystis Pyrifera (Kelp) ✔ ✔ Macrocystis Pyrifera (Kelp) Blade/Pneumatocyst/Stipe Juice Extract

✔ ✔

Macrocystis Pyrifera (Kelp) Juice ✔ ✔ Macrocystis Pyrifera (Kelp) Protein ✔ ✔ Hizikia Fusiforme Extract (synonymous with Sargassum Fusiforme Extract)

✔ ✔

Sargassum Fusiforme Extract (synonymous with Hizikia Fusiforme Extract)

✔ ✔

Hizikia Fusiformis Water ✔ ✔ Hizikia Fusiformis Callus Culture Extract

✔ ✔


Laminaria Longissima Extract ✔ ✔ Undaria Pinnatifida Leaf/Stem Extract

✔ ✔

Undaria Pinnatifida Root Powder ✔ ✔ Ecklonia Cava Water ✔ Ascophyllum Nodosum ✔ - 4 week oral Nereocystis Leutkeana Extract ✔ Laminaria Cloustoni Extract (synonymous with Laminaria Hyperborea Extract)

✔

Laminaria Hyperborea Extract (synonymous with Laminaria Cloustoni Extract)

✔

Laminaria Digitata Powder ✔ Ascophyllum Nodosum Powder ✔ FucusVesiculosus ✔ Fucus Vesiculosus Powder ✔ Fucus Serratus Extract ✔ Fucus Spiralis Extract ✔ Halidrys Siliquosa Extract ✔ Pelvetia Canaliculata Extract ✔ Sargassum Filipendula Extract ✔ Sargassum Muticum Extract ✔ Sphacelaria Scoparia Extract (synonymous with Halopteris Scoparia Extract)

✔

Halopteris Scoparia Extract (synonymous with Sphacelaria Scoparia Extract)

✔

Cystoseira Tamariscifolia Extract ✔ Dictyopteris Polypodiodes Extract ✔ Cystoseira Amentacea/Caespitosa/Branchycarpa Extract

✔

Cystoseira Baccata Extract (synonymous with Phyllacantha Fibrosa)

✔

Phyllacantha Fibrosa Extract (synonymous with Cystoseira Baccata Extract)

✔

For the GRAS and Food column, as seen in the report, specific ingredient types were not reported, however, larger ingredient groups were reported. For example, Laminaria digitata since considered GRAS, it was assumed that the related ingredients, Laminaria Digitata Extract and Laminaria Digitata Powder, would also be considered GRAS. Ingredients in green text are not among the 6 previously proposed safe ingredients.


Remaining Ingredients Agarum Cribrosum Extract Cladosiphon Novae-Caledoniae Extract Cystoseira Balearica Extract (synonymous with Cystoseira Caespitosa Extract) Cystoseira Caespitosa Extract (synonymous with Cystoseira Balearica Extract) Cystoseira Compressa Extract Cystoseira Compressa Powder Dictyota Coriacea Extract Durvillaea Antarctica Extract Ecklonia Kurome Extract Ecklonia Kurome Powder Ecklonia/Laminaria Extract Ecklonia Maxima Extract Ecklonia Maxima Powder Ecklonia Radiata Extract Eisenia Arborea Extract Himanthalia Elongata Extract Himanthalia Elongata Powder Hydrolyzed Ecklonia Cava Extract Hydrolyzed Fucus Vesiculosus Extract Hydrolyzed Fucus Vesiculosus Protein Lessonia Nigrescens Extract Lessonia Nigrescens Powder Pelvetia Siliquosa Extract Saccharina Angustata Extract Saccharina Longicruris Extract Sargassum Fulvellum Extract Sargassum Glaucescens Extract Sargassum Horneri Extract Sargassum Pallidum Extract Sargassum Siliquastrum Extract Sargassum Thunbergii Extract Sargassum Vulgare Extract Undaria Peterseniana Extract
